Conjugated Photosensitizers for Imaging and PDT in Cancer Research
- João C. S. SimõesJoão C. S. SimõesInstitute of Chemistry, University of Neuchatel, Avenue de Bellevaux 51, CH-2000 Neuchatel, SwitzerlandBioEmission Technology Solutions, Alexandras Avenue 116, 11472 Athens, GreeceMore by João C. S. Simões,
- Sophia SarpakiSophia SarpakiBioEmission Technology Solutions, Alexandras Avenue 116, 11472 Athens, GreeceMore by Sophia Sarpaki,
- Panagiotis PapadimitroulasPanagiotis PapadimitroulasBioEmission Technology Solutions, Alexandras Avenue 116, 11472 Athens, GreeceMore by Panagiotis Papadimitroulas,
- Bruno Therrien*Bruno Therrien*Email: [email protected]Institute of Chemistry, University of Neuchatel, Avenue de Bellevaux 51, CH-2000 Neuchatel, SwitzerlandMore by Bruno Therrien, and
- George Loudos*George Loudos*Email [email protected]BioEmission Technology Solutions, Alexandras Avenue 116, 11472 Athens, GreeceMore by George Loudos
Copyright © 2020 American Chemical Society
Abstract
Early cancer detection and perfect understanding of the disease are imperative toward efficient treatments. It is straightforward that, for choosing a specific cancer treatment methodology, diagnostic agents undertake a critical role. Imaging is an extremely intriguing tool since it assumes a follow up to treatments to survey the accomplishment of the treatment and to recognize any conceivable repeating injuries. It also permits analysis of the disease, as well as to pursue treatment and monitor the possible changes that happen on the tumor. Likewise, it allows screening the adequacy of treatment and visualizing the state of the tumor. Additionally, when the treatment is finished, observing the patient is imperative to evaluate the treatment methodology and adjust the treatment if necessary. The goal of this review is to present an overview of conjugated photosensitizers for imaging and therapy.
1. Introduction
ARTICLE SECTIONS
Photodynamic therapy (PDT) is an attractive cancer theranostic platform, mainly due to its precise controllability, minimal invasiveness, and high spatiotemporal accuracy.(1) It works by combining photosensitizers (PS) with negligible cytotoxicity and excitation light in compatible doses to produce cytotoxic reactive oxygen species (ROS), which eradicate cancer cells.(2) PDT presents, therefore, several unique and distinct characteristics, which make it a very advantageous therapy not only as a stand-alone treatment but also in combination with other established modalities.
Although conventional imaging remains critical to the management of patients with cancer, molecular imaging can provide additional information. Imaging, in such manner, is an extremely intriguing tool since it is not only assuming an essential role after treatment to access its success and recognize any conceivable repeating injuries, but also because it allows an examination of the disease and to investigate whether the behavior of the tumor has changed. Additionally, when the treatment is finished, observing the patient is vital in order to evaluate the outcome and, if necessary, to revise the protocol.(3) Imaging, in combination with PDT, may therefore be used not only for research but also as a tool for studying basic PDT mechanisms, developing models of diseases, understanding PDT tissue interactions,(4,5) and even as a therapy response.(6) Moreover, it can provide a basis to establish the prospect of success of new therapeutic approaches.(7−11)
PDT imaging can be divided into different modalities: optical, ultrasound, magnetic resonance, and nuclear imaging, according to the mechanism of action.(12) This can either be through radioactive compounds that produce a flag on a screen (PET or SPECT), by utilization of nonradioactive materials that may enhance the contrast of tumors (computer tomography (CT) and magnetic resonance imaging (MRI)) or through acoustic (ultrasound and photoacoustic) and fluorescence signals upon activation (Figure 1).
Figure 1
Figure 1. Imaging applications in photodynamic therapy.
While both, optical and nonoptical imaging, have been used to monitor PDT, the outcomes are often assessed too late, usually when the disease has progressed more than expected. This creates a new challenge for developing online or early monitoring strategies to envision as soon as possible a new approach to treat a disease.(13) Imaging techniques combined with PDT offer new opportunities for the treatment of different cancers. This concept introduces the so-called theranostic agent, a single compound that inherently possesses both imaging and treatment properties, allowing for the visualization of the problem while being able to treat the condition.(3,14) These modalities have correlative properties that make them appropriate for various kinds of in vivo imaging applications. They are overall conceivable to be conjugated with PDT agents so as to accomplish a definitive objective of having a single agent that does “all”.(3,15)
Theranostic agents are commonly divided into two groups according to their design: (1) an agent with both properties, imaging and therapeutic, and (2) double-functionalized nanoparticles (theranostic particles) that are modified with an assortment of imaging and therapeutic moieties.(3) Exploiting the same biodistribution such theranostic agents can pave the way to personalized medicine (Figure 2).(16−19) Due to the development of instruments for imaging and PDT treatment, several imaging and therapeutic modalities have been combined, using different assembly strategies, to develop novel theranostic agents.(20)
Figure 2
Figure 2. Cartoon depicting personalized medicine with theranostic agents.
2. Basic Principles of Photodynamic Therapy (PDT) and Photosensitizers
ARTICLE SECTIONS
2.1. Photodynamic Therapy (PDT)
The true potential of PDT was only realized after the extensive work of Dougherty and co-workers who, between 1975 and 1980, reported a complete cure of malignant tumors by combining an HpD (hematoporphyrin derivative) and red light.(21) Initially, it was applied in a breast cancer model and later in patients with skin, prostate, breast, or colon tumors. These promising results were later confirmed in clinical trials with improved versions of HpDs in patients with skin or bladder cancer. At the same time, Weishaupt and his colleagues postulated that singlet oxygen (1O2) generated in PDT was the cytotoxic agent responsible for the destruction of tumor cells.(22,23) Finally, in 1993, a landmark for PDT was achieved with the regulatory approval in Canada of porfimer sodium, a semipurified version of HpD, for the treatment of bladder cancer.
Light, oxygen, and PS precise cooperation are key for the efficacy of PDT to trigger the production of ROS, responsible for the inactivation and destruction of tumor cells. Furthermore, PDT provides spatiotemporal control through the photosensitizer and the light source.(13) The PS can reach the tumor compartment utilizing various targeted methodologies,(24) such as immunoconjugates or nanotechnologies.(25) A localized light activation ensures an optimal treatment, thus sparing surrounding tissues. While a specific location of light illumination provides spatial control, a time delay between PS administration and light irradiation provides a temporal control of the therapy.
Nevertheless, the combination of light, oxygen, and PS represents a great challenge in the optimization of therapeutic protocols. To obtain the desired therapeutic effect, a great number of factors should be considered, namely, the type of PS, the dose administered, the intracellular location, the drug to light interval (DLI), the total light dose applied, its wavelength and fluence rate, tumor characteristics, and local availability of oxygen. Since the PS is only activated in the presence of light, PDT presents several advantages over other conventional cancer treatments such as low systemic toxicity and the capability to destroy tumor cells selectively. Furthermore, it can also be applied in combination with other therapeutic modalities and is often cheaper than other cancer treatments.(26,27) On the other hand, PDT presents some disadvantages including the fact that most of the PS used in PDT are hydrophobic molecules, they show a poor cell specificity, and light penetration through tissues is minimal, thus limiting PDT treatments to superficial tumors such as skin cancer, nasopharyngeal cancer, and oral cancer.(28−32)
2.2. Photosensitizers in PDT
When developing new photosensitizers, there are a series of advantages and limitations that we can find. The limitations include photosensitivity after treatment, the fact that the treatment efficacy depends on optimal light activation to the tumor, and the presence of oxygen remains crucial to PDT. Another big disadvantage is that no current photosensitizer can treat metastatic cancers.(33) The advantages, on the other side, make for a compelling case for the continuation of the development of such compounds. These include fewer adverse effects and little invasiveness, short treatment time and selectivity, and lower costs than other treatments. Other advantages include the following: it can be used in outpatient settings, can be applied multiple times, and leaves little or no scarring after healing.(33)
A PS should, ideally, be a single and pure compound that accumulates preferentially in tumors. At the same time, it should have low toxicity in the dark to minimize phototoxic side effects, and it should be rapidly eliminated from the body.(27,34) To reach target cells, the PS needs a good balance between hydrophilicity and lipophilicity. Indeed, it must possess amphiphilicity. An ideal photosensitizing agent ought to have a high absorption peak between 600 and 800 nm (red to deep-red region). Absorption of photons at higher wavelengths (>800 nm) does not provide enough energy to excite oxygen to its singlet state and accordingly to generate sufficient ROS. These characteristics as well as others are summarized in Figure 3.
Figure 3
Figure 3. Ideal characteristics of photosensitizers.
In addition, a PS must have good photophysical properties, such as high quantum yields of triplet state formation, high singlet oxygen production, and an appropriate triplet lifetime. The triplet lifetime is crucial to allow the PS to interact with oxygen and other substrates in view to generate ROS.(27,34) Moreover, PSs should have good absorption between 600 and 800 nm to ensure strong light penetration into tissues. Therefore, agents absorbing strongly in the red, such as chlorins, bacteriochlorins, and phthalocyanins, are more suitable for PDT treatments. However, most known PSs do not possess all requirements. In the past few years, efforts have been focused on the development of PSs that can be activated with the light of a longer wavelength, with mild photosensitivity and high tumor specificity. Tetrapyrrole-based structures seem to gather most of these characteristics, making them the best option for PS when compared with other classes of molecules.
Many different molecular structures have been studied for PDT (Figure 4), including some natural products such as hyperacin,(35−37) curcumin,(38−41) hypocrellin(42,43) and riboflavin,(44−47) as well as synthetic dyes. When it comes to synthetic dyes, the most commonly studied are phenothiazinium salts such as Methylene Blue(48) and Toluidine Blue,(49) which have been widely studied both for antimicrobial applications(50) and, less often, anticancer activity.(51) Rose Bengal, which has a long history as a photoactive dye and has been explored for antimicrobial applications,(52) tissue bonding applications,(53) and anticancer applications is another example.(54) Squaraine and BODIPY dyes, with delocalized systems of molecular orbitals, provide good absorption in the visible range.(55)
Figure 4
Figure 4. Structures of photosensitizers currently used in PDT.
Most BODIPY dyes have the right characteristics, such as a low dark toxicity, a good cellular uptake, a high extinction coefficient, and a low quantum yield for photobleaching, which make them good PDT agents. However, some modifications can be made to their structure in order to enhance intersystem crossing (ISC) and prevent photodamage in PDT, which is thought to occur predominantly via triplet excited states. Spin-coupling to heavy atoms (“heavy atom effect”) is a common modification. Generally, the addition of heavy atoms occurs at positions that will not disrupt the planarity of the dye. An appropriate placing of heavy atoms on a BODIPY core promotes spin–orbit coupling, without any energy loss from excited states.(56) In the case of Rose Bengal, the introduction of halogens into the rings, such as bromine or iodine, seems to increase the triplet yield of the molecule by facilitating intersystem crossing. In a similar manner, the introduction of iodine into the delocalized system of squarines also increases the triplet yield.
Other synthetic dyes include phenalenones,(57) often used as a standard for the generation of 1O2 and recently developed into an antimicrobial PS,(58,59) and coordinated to transition metals. These are a relatively new class of PSs. Ruthenium(II) polypyridyl complexes are perhaps the most studied,(60) although other ruthenium,(61) rhodium,(62) and cyclometalated iridium(63) complexes have also been studied. There is also evidence that luminescent platinum(II) and gold(III) complexes can act as PSs.(64) In addition to these structures, nowadays, most PSs utilized in PDT (Figure 5 and Table 1) show a tetrapyrrole structure.
Table 1. PSs Currently Used in Clinics or Under Clinical Trials(73)
| generic name | chemical name | excitation wavelength (nm) | application | manufacturer | ||
|---|---|---|---|---|---|---|
| clinically approved | first generation | photofrin | porfimer sodium | 630 | esophageal cancer, lung adenocarcinoma, endobronchial cancer | Axcan Pharma, Canada |
| second generation | ameluz/levulan | aminolevulinic acid hydrochloride | 635 | mild to moderate actinic keratosis | DUSA, USA | |
| foscan | temoporfin | 652 | advanced head and neck cancer | Biolitec, Germany | ||
| laserphyrin | aspartyl chlorin | 664 | Early centrally located lung cancer | Meiji Seika, Japan | ||
| metvix/metvixia | methyl aminolevulinate | 570–670 | nonhyperkeratotic actinic keratosis, basal cell carcinoma | Galderma, UK | ||
| redaporphine | 749 | biliary tract cancer | Luzitin, Portugal | |||
| visudyne | verteporfin | 690 | age-related macular degeneration | Novartis, Switzerland | ||
| under clinical trials | antrin | motexafin lutetium | 732 | coronary artery disease | Pharmacyclics | |
| fotolon | 665 | nasopharyngeal sarcoma | Apocare Pharam, Germany | |||
| photoclor | 664 | head and neck cancer | Rosewell Park | |||
| photosens | sulfontaed alumunium phthalocyanines | 675 | age-related macular degeneration | Russia | ||
| photrex | 664 | age-related macular degeneration | Miravant, USA | |||
| radachlorin | 662 | skin cancer | Rada-pharma, Russia | |||
| talaporfin | l-aspartyk chlorin e6 | 664 | colorectal neoplasms, liver metastasis | Novartis, Switzerland | ||
| TOOKAD | padeliporfin | 762 | prostate cancer | Negma-Lerads |
Figure 5
Figure 5. Most commonly used PSs in the clinic.
It is possible to categorize the photosensitizers into three generations, especially with regards to porphyrin-based PSs. Porfimer sodium and the hematoporphyrin derivative (HpD) are known as the first generation of photosensitizers.(22,65) Porfimer sodium shows many drawbacks, such as a poor light absorption at the maximum wavelength (εmax at 630 nm), a low molar extinction coefficient (∼3000 M–1 cm–1), and a slow clearance, which causes prolonged photosensitivity of the skin after treatment.(65−68)
While a photodynamic impact can be achieved with porfimer sodium, efficiency can be improved by red-shifting the absorbance band and by increasing the absorbance at longer wavelengths. There has been a noteworthy exertion among therapeutic physicists to find second-generation PSs, and numerous compounds have been proposed as potent anticancer agents for PDT.(34) The so-called second generation of photosensitizers, which include various derivatives of porphyrins, phthalocyanines, naphthalocyanines, chlorins, and bacteriochlorins, was created from not only just the need to overcome drawbacks but also to increase the formation of singlet oxygen (1O2), through a type II process.(69,70)
When the wavelength is higher, the light penetrates through tissues deeper; therefore, PSs with strong absorbance in the deep-red region, such as chlorins, bacteriochlorins, and phthalocyanins, can have a better impact on tumors. Chlorin derivatives show an intense absorption band around 650 nm, which make them good candidates for PDT applications. These PSs with increased light penetration were classified as second-generation photosensitizers.(71)
An early example is temoporfin, which was approved in Europe in 2001. This chlorin derivative reduces the skin post-treatment photosensitivity by at least a factor of two, from 4 to 12 weeks with porfimer sodium to only 2 to 4 weeks. Moreover, because it possesses an increased light absorption at a longer wavelength (652 nm), the light dose required for treatment is reduced by a factor of 10. Although showing significant progress when compared to sodium porfimer, some other aspects needed to improve such as pharmacokinetic profiles and higher phototherapeutic indices, as well as solubility.(72) The side effects of the second generation of PSs caused by nonspecific localization, and the need for better pharmacokinetic profiles gave rise to the development of a third generation of photosensitizers: PSs with amphiphilic properties appropriate for diffusion through the lipid barrier and for endocellular localization.(73)
Therefore, to improve the efficacy of PSs in PDT, the so-called third generation of PSs must show a longer wavelength activation and a better selectivity for tumor tissues. To achieve these goals, conjugation of targeting molecules (such as antibodies) to the PS, encapsulation of a PS into carriers (such as liposomes, micelles, or nanoparticles), or functionalization with prodrugs that get activated only at the tumor site, is among the new strategies employed.(65−68) The main goals being the improvement of specificity and efficacy, reduction of off-target accumulations, and optimization of the pharmacokinetic.
In order to reduce the impact on adjacent tissues, the concept of prodrug has been evaluated. The strategy consists of the administration of a PS in an inactive form, which will become active only after reaching the target. The activation will be triggered by proteases, the pH, or another biological response. A PS producing singlet oxygen in a specific environment, acidic conditions, for example, will have a stronger impact on tumors where the pH is lower.(73) Such activatable photosensitizers combine the concept of local treatment and personalized therapy, the main objective being to display minimal phototoxicity when off-target, and high activity in the targeted tissue to increase PDT selectivity.(74) Although the strategy of activatable agents seems to be of great interest for the future of photodynamic therapy, the main strategy applied nowadays still seems to be the functionalization of these molecules through conjugation with biomolecules and carriers such as porphysomes, quantum dots, nanoparticles, and targeting moieties.
2.3. Functionalization of PSs
Incorporation of hydrophilic groups on the PS, such as HSO3–, COO–, and NR4+, increases the water solubility, but the delivery of lipophilic PSs to target cells remains an important PDT goal.(75,76) To achieve that goal, different types of functionalization of PS can be performed, usually through the conjugation with other molecules. The choice of the conjugates is driven by the tumor microenvironment, such as hypoxia,(77) enzymes,(78) leaky vasculature,(79,80) and receptors overexpressed by cancer cells.(81,82)
Lately, certain limitations of potent PSs, such as (i) poor solubility in aqueous media, (ii) high potency for aggregations, and/or (iii) undesired interactions with proteins or biomolecules in aqueous media, in combination to the rapid advances in nanotechnology, led to the development of another round of the third generation of PSs, which are encapsulated to the nanostructure,(83−87) with the most commonly used nanoparticles being listed in Table 2.
Table 2. Clinically Approved Nanoparticles(130)
| type | agent | modality | indication | trade name | |
|---|---|---|---|---|---|
| clinically approved | sulfur colloid | 99mTc | SPECT | lymphoscintigraphy, bone marrow, gastrointestinal, liver, and spleen | Technecoll (US) |
| albumin colloid | 99mTc | SPECT | lymphoscintigraphy, inflammation imaging, melanoma, prostate | Nanocoll (EU) | |
| SnF2 colloid | 99mTc | SPECT | lymphoscintigraphy, gastrointestinal, liver, and spleen | Hepatate (France) | |
| Re2S7 colloid | 99mTc | SPECT | lymphoscintigraphy, gastrointestinal, melanoma, prostate | Nanocis (EU) | |
| albumin colloid | 99mTc | SPECT | lymphoscintigraphy of breast | Senti-Scint | |
| dextran-coated iron oxide (ferumoxide) | Fe2+ Fe3+2O4 (Fe3+ Fe2+2)O4 | MRI | mononuclear phagocyte system imaging, cellular labeling | Feridex (US), Endorem (Britain) | |
| carboxydextran-coated iron oxide (ferucarbotran) | Fe2+ Fe3+2O4 (Fe3+ Fe2+2)O4 | MRI | lymph node imaging, perfusion imaging | Sinerem (EU), Combidex (US) | |
| carboxydextran-coated iron oxide (ferucarbotran) | γ-Fe2O3 | MRI | hepatocellular carcinoma, cell labeling | Resovist (US, EU), Cliavist (France) | |
| polyglucose sorbitol carboxymethyl ether-coated iron oxide (ferumoxytol) | γ-Fe2O3 | MRI | iron-deficiency anemia, off-label uses in imaging | Faraheme (US) | |
| under clinical trials | sulfur colloid | 99mTc | SPECT | colon cancer | |
| sulfur colloid | 99mTc | SPECT | cancer | ||
| sulfur colloid | 99mTc | SPECT | head and throat cancer | ||
| gold | nanoshell | photothermal | head and neck cancer | ||
| silica | 124I and Cy5 | PET and optical | melanoma | ||
| iron oxide | ferumoxytol | MRI | glioma | ||
| iron oxide | ferumoxytol | MRI | pancreatic cancer | ||
| iron oxide | ferumoxide | MRI | inflammation | ||
| iron oxide | ferumoxytol | MRI | myocardial infarction |
Medicinal nanoparticles (NPs) are drug-loaded, and their overall size does not exceed the 100 nm in order to cross effectively physiological barriers in vivo.(91,92) Appropriate modification of NPs enables improved solubility, excess in drug loading, and to control drug release and enhancing their imaging modalities.(92−94) These interesting and sometimes unexpected properties of nanoparticles are largely due to their high surface-area-to-volume ratio. Introduction of different functional groups at the surface of NPs provide a variety of chemical properties.(91) In other words, the surface or core of the nanoparticle might be loaded with various agents, allowing the use in multiple applications simultaneously (such as imaging and therapy).(95−97) A common example of indirect PS functionalization is the usage of peptide linkages that can be cut by metalloproteinases (MMP’s), which are ordinarily abundant in an assortment of tumors. Nanoparticles can likewise help in the delivery of hard-to-formulate drugs within water-based solutions, by either protective biopolymer coating or encapsulation.(3)
Nanoparticles can also be surface-covered with polymers such as poly(lactic-co-glycolic corrosive) (PLGA) or polyethylene glycol (PEG) for increased tumor selectivity.(98) The surface can be decorated with drugs, pro-drugs, contrast agents, or a mixture of different elements.(99) Optimally, the monitoring of treatments (before, during, after) is conducted by the contrast agent. Nanoparticles can also be loaded with drugs or prodrugs (peripherally or internally).(99) Such theranostic nanoparticles can be tweaked to release the drug based on tumor microenvironment conditions.(99−102) Indeed, many tumors possess a poor blood vessel system, of leaky, dilated, and irregular shapes, which allow large molecules to reach the tumor.(103) Then, when inside, the lack of efficient lymphatic drainage traps the NPs in the tumor. These two phenomena are known as the enhanced permeability and retention effect (EPR).(103,104) The surface of the NPs can be functionalized with targeting agents to interact with overexpressed tumor-related receptors.(105) Targeting biomolecules can be combined so that one functional group may allow the nanoparticle internalization by endocytosis, while another functional group targets a specific receptor before drug release.(106)
Recent studies have demonstrated the possibility of using metal-based nanoparticles as photosensitizers, up-conversion tools delivery, and vehicles.(107) Moreover, metal-based NPs show good sizes and shapes to ensure prolonged activity and biodistribution. Studies dealing with nanoparticles based on molybdenum oxide, TiO2, ZnO, and tungsten oxide as photosensitizers in PDT have been conducted in recent years.(108,109)
The first investigation of nanoscaled metal–organic frameworks (MOF) in PDT was reported by Lu et al. in 2014.(110) Their study suggests that the Hf–porphyrin nanoscale metal–organic framework (DBP–UiO) is an excellent photosensitizer in PDT treatments of resistant head and neck cancers. The DBP–UiO framework shows enhanced in vitro and in vivo PDT efficacy. Following this initial study, other applications of nanoscaled MOFs in PDT were reported.(111) MOFs have indeed become popular metal-based nanoparticles for PDT applications.
A very common conjugation of photosensitizers is with porphysomes. Porphysomes are derived from porphyrin–lipid bilayers, and they show a high static quenching effect. In addition, they have a structure and a loading capacity similar to those observed for liposomes. Most importantly, they have a high porphyrin payload that is advantageous for PDT treatment, while being biocompatible, nontoxic, and biodegradable.(112)
Jin et al. have constructed folate-porphysomes by incorporating a small percentage of folate conjugate lipids in porphysome formulation. This allowed FR-mediated cell uptake of nanoparticles, which, subsequently, resulted in a rapid disruption in cells upon activation of porphyrin fluorescence and production of ROS. The irradiation of the folate porphysomes increases folate receptor-selectivity and ultimately PDT efficacy. Once systematically administrated to FR-positive tumor-bearing mice, the folate-porphysomes were reducing the tumor size and increasing the survival rate. Furthermore, such targeting-porphysome formulation facilitates the introduction of additional targeting moieties to realize disease-specific and personalized PDT treatments.
Similarly, Lovell et al. developed porphysomes with a higher quenching capacity than the PS alone.(113) Located inside a simple bilayer, the porphyrin–lipid orientation promotes porphyrin interaction and quenching. However, after loading porphyrins into the nanocarrier, the fluorescence response was regained, thus confirming the benefit of these combinations.
Another example of a successful porphysome design was published by Philp et al., in which porphysomes were used to monitor in real time the resection of primary tumors, lymph nodes, and abdominal metastases in rabbits.(114) Another proof of the diagnostic ability of nanoparticles was reported by Ng et al., who employed bacteriopheophorbide as a fluorescent energy acceptor in a self-sensing porphysome (FRETysome).(115) Following subcutaneous injection in mice, the presence of FRETysome has permitted to image the tumor. Moreover, they observed after 24 and 48 h postinjection the persistence of nanovesicles at the tumor site.(116)
Several research groups have recently focused their interest in the functionalization of “quantum dots” QDs with PDT agents. Nanostructured semiconductor materials were first applied in heterogeneous photocatalysis in the 1980s, and their unique properties have raised attention.(88,117−120) Scientists used these nanocrystals as PSs, due to their ability to selectively transfer energy and to produce light over a broad range of wavelengths, which can be optimized to the appropriate wavelength for PS excitation.(121−125) Unlike most organic photosensitizers, QDs do not have metastable excited states, which can promote effective energy transfer, and therefore, distinct processes are expected to occur, thus yielding reactive oxygen species in a different way.(126)
Wang et al. developed a water-soluble and pH/H2O2 responsive silicon QDs-based nanocomplex and explored their applications in PDT.(127) Silicon is not only an outstanding semiconductor but also a promising fluorescent probe for targeting and imaging cancer cells. The developed QDs could not only deliver more photosensitizers but also image the tumor by fluorescence. In vivo experiments have confirmed that, under light exposure, the growth of tumor was effectively repressed.(127)
When administered individually, both PSs and QDs have advantages and limitations. Some properties such as NIR absorption, broad absorption bands, and photostability are required for PDT. Surprisingly, the actual PSs present disadvantages when compared to the unique optical properties of QDs, such as narrow absorption band, poor photostability, and visible light absorption.(128) QDs’ properties such as efficient light outputs and the capacity of tuning their absorption and emission bands gave them an exceptional photoresistance. This allows light excitation for continuous ROS production either via type I or type II processes and accordingly ensures prolonged phototherapies.(129)
Nanotechnology in PDT has created new opportunities and new modalities in the field by providing efficient nanoscale PSs delivery systems. While allowing a controlled release of drug and efficient uptake by cells, their surface area can be modified with functional groups for additional chemical/biochemical properties, which together improve the treatment efficacy and minimize side effects associated with classic PDT. Moreover, it has been demonstrated that it is conceivable to have a single nanoparticle formulation conveying a lower dose of the imaging probe and a high payload of the therapeutic drug, meaning that nanocarriers can positively modulate biodistribution and pharmacokinetic profiles of the drug formulations overcoming the current drawback of most molecular theranostic agents.(130−132) To date, there has been a high number of different synthetic strategies,(133) which only consolidates the potential interest in NPs, both as drug carriers and as imaging agents. Hence, many tactics have been used to incorporate PSs into polymers, gold nanoparticles, magnetic and silica nanoparticles, as well as other various delivery carriers such as liposomes, quantum dots, and so on.(134−137) These NPs show high selectivity, high efficacy, and limited side effects.(138) Currently, there are only a few nanoparticle-based theranostic platforms tested in clinical trials, but this might change in the near future.(139,140)
2.4. Active and Passive Targeting of PSs
One of the main challenges in PDT is linked to drug delivery and targeting.(84,85) An ideal PS is delivered in therapeutic concentrations to only the target cells, while healthy cells remain untouched. This basic concept ensures minimal side effects, when keeping and efficient PDT treatment.(85,133) For more than 20 years, intensive efforts have been put in the development of targeted photodynamic therapy. The subcellular localization of the PS in mitochondria, lysosomes, endoplasmic reticulum, and plasma membrane (different organelles) plays a crucial role in the cell death mechanism involved (apoptotic, necrotic, and autophagy-associated cell death). For example, the majority of the clinically approved photosensitizers, temoporfin,(138) porfimer sodium,(141) and verteporfin,(142) already partially localize to the mitochondria,(143) which is considered as one of the most pivotal subcellular organelles in eukaryotic cells.(144) Moreover, defects or dysfunctions of mitochondria are connected to cancer progression and programmed cell death. Therefore, intensive research has been done toward the development of mitochondria-targeting therapeutics and diagnosis, which can effectively overcome tumor hypoxia, evade MDR, improve photothermal cancer treatment efficiency, and so on.(145,146) A study by Sibrian-Vazquez et al. demonstrated an increased localization of guanidinium and bisguanidinium porphyrin derivatives to the mitochondria, due to the positive charge of the compounds.(147)
One of the two main approaches to accomplish tumor-targeted PDT is by covalent conjugation of the photosensitizer with targeting biomolecules (Figure 6). These include proteins (essentially antibodies and their fragments), peptides, nucleic acids, and small molecules (biotin, folic acid, gefitinib, etc.). This is called active tumor targeting and refers to specific interactions at the molecular level between the drug/nanocarrier and target cells, usually through specific recognition and ligand–receptor interactions.(148,149)
Figure 6
Figure 6. Two main strategies to accomplish tumor-targeted PDT.
Active targeting can be further separated in vascular targeting and tumor targeting. Both can work simultaneously to achieve better therapeutic efficacy. The first aims to eradicate tumorous blood vessels, which supply nutrients and oxygen to the tumors, by facilitating the accumulation of nanoparticles in vascular tissues.(150) Tumor targeting, on the other hand, increases the accumulation and cellular uptake of nanoparticles by selecting an appropriate receptor–ligand or antigen–antibody pairing. This is one of the most important issues in active targeting. Tumor cell markers must have two defining characteristics: (1) overexpression on the surface of tumor cells while being mostly quiescent on the surface of a normal, noncancerous cell and, (2) at the same time, should be selectively identified and bound by corresponding ligands.(150) Only in this way, they can be used as sites (i.e., the receptor) for the targeted delivery of specific drugs (such as anticancer drugs or photosensitizers). Targeting moieties can be separated into different categories: nonprotein small molecules, receptor-specific peptides, aptamers, and a variety of proteins, such as transferrins, lectins, and antibodies.(151,152)
Several tumor cell markers have been explored for active photodynamic targeting, including transferrin receptors (TR), folic acid receptors (FR), glucose transporters, growth factor receptors, LDL receptors, integrin receptors, and insulin receptors. Other potential tumor cell markers often include glycoproteins, such as lung cancer tumor markers (i.e., CEA, Cyfra21–1, and NSE), gastrointestinal tumor markers (i.e., CEA, CA199, the CA242 group, and CA724), breast cancer markers (CA153), ovarian cancer markers (CA125), hepatocellular carcinoma markers (AFP), prostate cancer markers (PSA), and choriocarcinoma markers (HCG).(150)
Recently, for example, Kim et al. synthesized a tumor penetrating trastuzumab (Tra) derivative by chemical conjugation to chlorin e6 (Ce6).(153) Tra is a monoclonal antibody used for treating human epidermal growth factor receptor 2 (HER2) overexpressing cancers.(154) The ability of Ce6 to generate ROS and the targeting of HER2 receptors increased the internalization of the conjugated PS. In this derivative, Tra and Ce6 were linked by a maleimide-poly(ethylene glycol) spacer. A confocal microscopy study showed that the fluorescence associated with Ce6 was only detected for the HER2-positive cell lines (SK-BR-3, BT-474), thus confirming selectivity. In comparison, the Ce6-Tra conjugate compound penetrated more deeply, which can contribute to better destruction of dense tumor tissue. In this system, visualization and PDT treatment were combined.(155)
When it comes to conjugated biomolecules, several types have been investigated, including receptor-specific peptides, transferrins, antibodies, oligonucleotide aptamers, and nonprotein small molecules, which include vitamins (e.g., folic acid, vitamin D, vitamin E, and vitamin B), retinoic acid, steroids, and other hormones. Some very effective binders include those interacting preferentially to low-density lipoprotein (LDL), suggesting that upregulated LDL receptors found on tumor cells are important.(156) Consequently, studies dealing with PSs covalently linked to molecules with affinity for neoplasia or to receptors expressed on specific tumors have been published.(157) In particular, those involving small molecular-based targeting drugs have received a great deal of attention in the design of targeted photosensitizers for cancer therapeutics.(158)
Conjugation of PSs to tumor-specific biomolecules such as monoclonal antibodies, epidermal growth factor, and small molecules (e.g., short peptides or peptidomimetics) provides another promising strategy to increase selectivity. Incorporation of functional groups to target specific receptors associated with cancer is, indeed, a common strategy to increase the efficiency of PSs (Figure 7). As mentioned before, an overexpressed receptor that has already been explored for the targeting of cancer cells is the folate receptor α.(159)
Figure 7
Figure 7. Receptor-targeted approach in PDT.
Another example of this kind of functionalization for targeting can be found in the work of Soukos et al., where a monoclonal antibody was conjugated to Ce6 as a tumor-specific targeting agent for imaging and therapy in a hamster cheek pouch carcinogenesis model.(9) This “photoimmunoconjugate” derivative (PIC), as it was defined, increases the specific delivery of the PS. In this study, EGFR, which is overexpressed in several human tumors, was the target. The anti-EGFR monoclonal antibody (C225) was selected and attached to Ce6. Then, the PIC was used as a diagnostic platform and monitoring tool to determine the therapeutic response. The same antibody (C225) was also conjugated to the benzoporphyrin derivative (BPD, verteporfin), thus providing another PIC derivative.(160)
Besides antibody-based PICs, small molecules and peptides can also be introduced to PSs. For example, Choi et al. introduced a membrane-penetrating arginine oligopeptide (R7) on 5-[4-carboxyphenyl]-10,15,20-triphenyl-2,3-dihydroxychlorin (TPC), in view to enhance cellular uptakes.(161) For similar reasons, new kinds of PSs with high water solubility, as well as with one or more functional groups for conjugation with biological agents, have been prepared by Li et al.(122) They have reported on the synthesis and characterization of asymmetrically substituted highly water-soluble phthalocyanines (Pc), with two different types of peripheral substituents: one reactive group for conjugation and the others for water solubility (Figure 8).
Figure 8
Figure 8. Structures of conjugated PSs.
Passive targeting is occasionally interpreted as physical targeting, which exploits the physiological and morphological differences between healthy and tumor tissues to achieve tumor selectivity and preferential accumulation of PSs. As mentioned previously, nanocarriers provide the potential for improvement of PS delivery to the target area to maximize PDT efficacy. Due to the uncontrolled proliferation of tumor cells, solid tumors have an abnormal tissue composition and architecture, which limit the uptake and distribution of drugs.(162) While rapid vascularization promotes fast-growing tumor sites, inflamed tissues embrace a leaky and defective architecture, thus leading to the enhanced permeability and retention (EPR) effect.(163,164) In addition, there is an accumulation of drugs due to inefficient lymphatic drainage, which make it harder for tumor sites to clear nanoparticles.(164)
Hyperproliferative tumor cells have a high metabolic rate and keep growing despite limited oxygen and nutrients. Therefore, in order to maintain its activity, tumor cells employ an enhanced level of anaerobic glycolysis, which produces a large quantity of lactic acid, resulting in intratumoral hypoxia and a lower pH environment.(165) The accumulation of PSs in tumors is known to be enhanced as its hydrophobicity increases. This is due to the fact that hydrophilic molecules are retained in the blood circulation system, while hydrophobic molecules tend to extravasate and accumulate in tumor tissues. PSs, however, generally have large π-conjugation domains for high quantum yields and effective energy absorption, which enable most classical PSs to easily aggregate in an aqueous environment. For this reason, these PSs are not suitable for intravenous administration, and further functionalization is needed, usually through the conjugation with a nanocarrier.
Since accumulation at the tumor involves a passive process requiring a long circulation half-life, the targeted delivery of PS-loaded nanocarriers is largely dependent on the biophysical and morphological properties of the nanocarrier. These properties include the material composition, morphology, hydrodynamic size, and surface charge.(166) The hydrodynamic size affects NP concentrations in the vessel, NP permeability, and clearance from the body.(167,168)
Another important factor concerning passive targeting is the surface properties. In vivo experiments have shown that hydrophobicity and surface charge affect the fate of nanoparticles and determines their behavior with plasma proteins, cells of the immune system, and nontargeted cells.(169)
3. Imaging and Therapy Techniques in PDT
ARTICLE SECTIONS
In the medical field, approval to run clinical trials is often a limiting step, and this is also true for the implementation of molecular imaging biomarkers.(170) However, it is undeniable that molecular imaging, if the modality is chosen correctly, is more efficient in a timely and resource manner when compared to other practices such as tissue dissection and histological analysis.(171) From all of the different imaging techniques used for PDT, optical imaging is more broadly studied due to the fluorescence properties of the PSs. For this reason, we cannot exclude from this review where we will also focus on nuclear medical imaging (PET/SPECT) due to the great potentials the authors believe it holds, even though other techniques like MRI(172−175) and ultrasound(176) have also been developed and extensively studied on PDT over the past decade. A summary of the most used imaging agents currently in medicine can be found in Table 3.
Table 3. Commonly Used Imaging Agents
| modality | agent | application |
|---|---|---|
| MRI | gadolinium | highlights areas of tumor or inflammation |
| PET/SPECT | [64Cu]Cu-ATSM | identify hypoxic tissue |
| [18F]FDG | radioactive sugar molecule (-[18F]-fluorodeoxyglucose) that shows the metabolic activity of tissues | |
| [18F]-fluoride | imaging of new bone formation | |
| [18F]FLT | 3′-deoxy-3′-[18F]-fluorothymidine allows to detect growth in the primary tumor; detect tumor response to treatment | |
| [18F]FMISO | [18F]-fluoromisonidazole is used to identify hypoxia | |
| [68Ga]Ga(III) | attaches to areas of inflammation, such as infection; attaches to areas of rapid cell division, such as cancer. | |
| technetium-99m | used to radiolabel many different common radiopharmaceuticals; most used in bone and heart scans | |
| thallium-201 | examine heart blood flow | |
| X-ray and CT imaging | barium | contrast agent used to enhance images of the abdomen and pelvis |
| gastrografin | same as barium but contains iodine instead | |
| iodine contrast agents | highlight blood vessels as well as the tissues of various organs; can be ionic or nonionic (less side effects) |
In addition, PSs are fundamentally theranostic agents when used for PDT treatments, since such compounds absorb and emit light upon activation. Hence, the fluorescence property is used for imaging to monitor tumor uptake. Moreover, the PS fluorescence holds promise for fluorescence-guided resection (FGR) treatment, which is approved in Europe for both brain(177) and bladder cancers,(178) Another advantage of using PSs for FGR is that it allows a posteriori follow-up of treatments.(179) The specificity of PDT presents itself as the same molecule that may do both, the therapeutic and imaging roles.
3.1. Optical Imaging
A pivotal role has already been played by optical imaging in PDT dosimetry.(13) The presence of PSs at the targeted location before PDT treatment was used to quantitatively monitor the fluctuation of fluorescence before and after treatment, thus showing a correlation between clinical response and fluorescence.(180) This different outcome was associated with photobleaching during the production of reactive oxygen species. Zhou et al. have also observed that the response to treatment is less influenced when the light dose is adjusted to PS uptake.(181) Such studies confirm the significance of fluorescence imaging in PDT dosimetry.(179)
The fluorescence property of PSs can also serve for imaging as most PSs upon activation emit light in the visible region. Moreover, as PSs have a tendency to accumulate better in neoplastic tissues, this approach, frequently named photodynamic diagnosis (PDD), is very much appropriated for selective visualization of tumors and to outline the frontiers between cancerous and healthy tissues. The ability to precisely define tumor boundaries is a crucial step during an optimization process of a surgical intervention. At the moment, this fluorescence imaging technique constitutes the majority of the imaging applications. Ensuring a cancer-free margin around cancerous tissues is a crucial factor in avoiding recurrence. Resection of excess healthy tissue, on the other hand, can have serious and severe implications for the patient. This is one of the reasons why combining imaging and therapy is so important, and why over the past years, there has been an increasing interest in the development of innovative theranostic agents.
Therefore, the preparation of PSs with high fluorescence intensity and excellent singlet oxygen (1O2) quantum yields (QYs) is particularly needed for cancer diagnosis and PDT. In this regard, diketopyrrolopyrrole (DPP) and boron dipyrromethene (BODIPY) are two kinds of a building block with great potential for PDT. Recently, Zou et al. have linked DPP and BODIPY through a series of donor–acceptor–donor (D–A–D) linkers, thus forming a DPPBDPI structured organic photosensitizer (Figure 9).(182) The results indicate that the synergistic effect, resulting from the combination of the two photosensitizers, can simultaneously increase the fluorescence intensity by 5.0% and the 1O2 QY by up to 80%.
Figure 9
Figure 9. Illustration of a theranostic agent for PDT with a D–A–D structure with enhanced 1O2, QYs, and fluorescence.
Upon nanoprecipitation, the DPPBDPI can form uniform nanoparticles (NPs), which display not only high phototoxicity but also insignificant dark toxicity toward HeLa cells. In vivo fluorescence imaging shows that the DPPBDPI-NPs target tumors rapidly and inhibit tumor growth upon PDT treatment, even at reduced doses (0.5 mg kg–1). The imaging and photodynamic behavior of DPPBDPI suggest a synergistic effect that can provide a novel theranostic platform for cancer diagnosis and PDT.
The high sensitivity of the method, the harmless nature of the agent, and the low cost of the procedure, makes optical imaging and detection an ideal imaging modality.(5) Among several characteristics, a potent PDD needs to have an intense absorption band in the red or the near-infrared (NIR) spectral region.(183) The optimal wavelength for PDT treatment must be a good compromise between activation and tissue penetration with low dispersion. Moreover, it should take into consideration the characteristics of the damaged tissue (location, lesion size, and accessibility). Because of these, and by utilizing near-infrared wavelengths (650–900 nm), which combine deep tissue with enough energy to excite the photosensitizer, fluorescence has ended up being an excellent asset for disease diagnostics and treatment.(184) It is easy to understand now how PSs are not limited exclusively to the therapeutic generation of singlet oxygen species, since numerous photosensitizers are additionally excellent fluorophores valuable for imaging, thus helping to characterize and to modify parameters amid PDT treatments. The tetrapyrrolic skeleton remains the most prominent structure for the development of photosensitizers. Tetrapyrrolic units show strong absorption in the visible region, and they possess an excellent photosensitizing ability to produce reactive oxygen species (ROS). In addition, the photophysical parameters of tetrapyrrolic units can be tuned by the insertion of metal ions or halogen atoms, like chlorine and fluorine, which induce macrocycle changes that modify the balance between fluorescence and intersystem crossing.(185−187)
The most fascinating and valuable imaging probes are photosensitizers that are nonphototoxic outside their destination and are only dynamic within the presence of a targeting molecule whereupon fluorescence and singlet oxygen production happen. Activatable photosensitizers (aPS) are perfect imaging probes since they share comparative activation mechanisms to fluorophores, and they can distinguish cancer cells from ordinary cells.(74) A few authors have researched into what they call “killer beacons” comprised of up to four modules: a fluorescent probe, a quencher, a linker, and a delivery vehicle, whose properties can be adjusted, modified, or joined to fill diverse needs (Figure 10). These beacons are based on a unique fluorescent photosensitizer linked to other functional groups. The dye should theoretically be hushed in the absence of the target, and its fluorescence re-established simply after the target is reached. To accomplish that, the PS must be linked to a quenching unit (Q) through a reasonable linker, which should keep the PS and quencher close enough to ensure fluorescence resonance energy transfer (FRET).
Figure 10
Figure 10. Principles behind a beacon system for post-PDT imaging of apoptosis.(184) The system is composed of four parts: a PS (violet dot), a folate delivery entity (blue dot), a caspase-3 cleavable linker (KGDEVDGSGK), and a quencher (red dot).
In another example of activatable photosensitizers, Stefflova et al. have designed and synthesized a folate receptor-targeted, hydrophilic, and pharmaco-modulated PDT agent (Figure 11).(184) This molecule, obtained after three synthetic steps from Spirulina algae, selectively detects and destroys cancer cells, while avoiding healthy tissues.(188) Pyropheophorbide-a (Pyro) is a fluorescent photosensitizer that can also be used for NIR imaging and PDT (over 50% quantum yield). The Photochlor derivative is in phase I/II of clinical trials. In this compound, the folate moiety serves as a guiding molecule to bring the photosensitizer to folate receptor (FR)-overexpressing cancer cells. The PS and guiding folate are linked by a short GDEVDGSGK peptide. This peptidic sequence is stable and water-soluble, thus preventing cleavage prior to reaching the target. Moreover, the length of the sequence ensures that no steric hindrance takes place. Lastly, it serves as a pharmaco-modulator for efficient delivery and reduced toxicity, and the system is easily modified to introduce other peptide sequences for different targeting.
Figure 11
Figure 11. Pyro-GDEVDGSGK-Folate comprising three components: pyropheophorbide-a (imaging and therapeutic agent), a peptide sequence (linker), and folate (delivery vehicle).
At last, photosensitizers’ efficiency can be upgraded by linking them with different particles that can deliver the entire cargo in malignant cells either nonspecifically or specifically, by focusing on “disease fingerprints”. For instance, PSs linked to oil dispersions, liposomes, or hydrophilic polymers (PEG) can be internalized to disease cells through passive diffusion or phagocytosis. Such carriers help to solubilize the PS in biological media (for intravenous infusion) and, furthermore, to increase uptake and retention by tumors.(184) The bifunctional chelator approach presents itself as one of the most interesting and viable solutions for a theranostic goal, using porphyrins as the perfect building blocks since they offer both a metal isotope chelator and a targeting vector.
3.2. PET/SPECT Imaging
Two main directions can be pursued for the radiolabeling of dyes, including photosensitizers: the first one focuses on hydrogen-3 and carbon-14 marking for biodistribution studies and tissue autoradiography, while the second focuses on labeling these molecules with a short half-life (the time is needed for a radioisotope to decay to its half) γ- or positron-emitting radionuclides for tumor imaging and nonintrusive quantitation of photosensitizers.(189) Nuclear medical imaging (NMI) strategies like positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are interesting complementary techniques, as they provide a further tissue penetration and decreased scattering of the produced signal.
In 1951, the first radiolabeled porphyrin system was prepared, introducing copper-64 in the core of protoporphyrin IX (Scheme 1). Soon after, hydrogen-3, carbon-14, palladium-109, sulfur-35, zinc-65, cobalt-57, and iodine-125 were likewise investigated. However, they are unacceptable for in vivo imaging as a result of their long half-lives or powerless gamma photon energy.(190) Currently, iodine-124, copper-64, and zinc-62 are the most promising radionuclides for PET imaging in PDT.(114,190−192)
Scheme 1
Scheme 1. Synthesis of [64Cu]CuPPIX (Protoporphyrin IX)(141)
In the 1980s, it was demonstrated that the in vivo biodistribution and pharmacokinetics of porphyrins are not affected by chelation with copper-64 in light of the fact that the copper molecule fits into the focal point of the tetrapyrrole ring without modifying the side chains that dictate the in vivo conduct. This made it conceivable to exploit porphyrins’ inborn capacity to chelate metals to fuse the radionuclide, taking into account the direct radiolabeling of photosensitizers with copper-64 without adjusting their conduct in vivo, which ultimately yields to exceptionally stable radiolabeled photonic nanoparticles.(193) Subsequently, the radiolabeling of metal complexes of porphyrins is the most encouraging strategy, the only issue being whether the metal has a radioactive species suitable for quantitative in vivo scanning and whether this can be exchanged with the nonradioactive species.
For nonmetallo-photosensitizers, the inclusion of the radioactive metal may change the biodistribution so that, for each metal-photosensitizer, combination biodistribution tests must be performed, normally with hydrogen-3 or carbon-14 labeling or quantitative fluorometry of excited tissues as a standard. In general, just as standard porphyrins, radiolabeled porphyrins accumulate in the tumor without changing the principle attributes of the host porphyrin molecules. Gallium-68(191) and copper-64(192,194,195) are promptly accessible and inexpensive metal isotopes, both appropriate for human PET imaging that may very well turn into the prime isotopes for radiolabeling porphyrins since complexation chemistry with the porphyrin core is quite straightforward, especially when it comes to copper-64.
While copper-64 marking has shown that, at least in animal tumor models, the fuse of this metal particle into the porphyrin ring does not significantly alter the uptake kinetics in tumors and healthy tissues. Marked differences between gallium-67 and technetium-99-labeled sulfonated phthalocyanines have shown that the metal ion modifies the dye conformation and thus may influence the molecular aggregation.(189,196) This leads to the conclusion that it is necessary to proceed with biodistribution investigations of radiolabeled analogues of photosensitizers at the beginning of in vivo studies.
On the other hand, the bifunctional chelator approach enables guided delivery of radioisotopes to selected cells by a kinetically and thermodynamically stable chelator conjugated to cancer-specific biomolecules such as antibodies, antibody fragments, peptides, or proteins. These systems exploit the overexpression of receptors and proteins on tumor cells. Some investigators accomplish this functionalization through the introduction of glucose and galactose moieties on the photosensitizer, thus culminating in an increased activity in tumor uptake.(190)
Since fluorine-18 is the most common radioisotope used in clinics, further research has been done regarding its potentials linkage to PSs. A dual-modality agent named [18F]-PET/fluorescence, in which both the positron-emitting and fluorescence properties are combined, has been developed by Li et al.(197) They used a BF2 unit, typically present in BODIPY dies, which can provide a [18F]-radiofluorination site. Through PET imaging, they observed 2 h post-injection, an accumulation of the radiolabeled PS in the liver and kidneys, as well as in the gall bladder. Considering the lipophilicity and electronic property of the radiolabeled system, an accumulation in these organs is not surprising, as the BF2 group possesses no targeting value.
The utilization of the fluorine-18 isotope in studies including antibodies and in photodynamic treatment (PDT) is, however, limited by its short half-life (110 min). In this regard, iodine-124 is considered a better choice for longitudinal imaging studies utilizing preclinical PET due to its half-life of 4.2 days. The labeling strategy for the iodine-124 isotope is well recognized, and it has been used in the labeling of an assortment of biologically active molecules.(198)
Developed by Roswell Park’s group, the [124I]-1′-3-(m-iodo-benzylox)ethylpyropheophorbide-a derived from chlorophyll-a has demonstrated in vivo PET-imaging capacity.(199) As a nonradioactive analogue of chlorophyll-a, it shows PDT efficiency, and therefore, it is an interesting candidate for PET imaging. With great pharmacokinetic and pharmacodynamics profiles, it can be utilized for imaging (PET/fluorescence) and PDT. Curiously, when comparing to nonradioactive compounds, the postloading of the iodinated analogues in polyacrylamide-based (PAA) nanoparticles (NPs) had a striking effect in the biodistribution. In mice, the imaging and treatment agents are better taken up by tumors, with decreased uptake in different organs, particularly in the spleen (Figure 12).
Figure 12
Figure 12. Multifunctional nanoplatform for cancer imaging and therapy with radiolabeled (124I) chlorophyll-a (right) and the nonradioactive analogue (left), showing the accumulation in the tumor.(3)
Focusing on another approach, some authors have detailed the labeling of phthalocyanines (Pc) with PET isotopes for both tumor imaging and drug development studies. Phthalocyanines, which are structurally like porphyrins, are powerful PSs in their own right because of their high singlet oxygen quantum yield and high activation wavelength (600–850 nm). Van Lier et al. have demonstrated that the level of Pc sulfonation strongly affects the level of complex aggregation and biodistribution, still conserving photosensitivity.(200) Consequently, they prepared a series of phthalocyanines with increasing sulfonate groups and radiolabeled each of them with copper-64 (Scheme 2). The tri- and tetra-sulfonated water-soluble phthalocyanines have shown rapid renal clearance on the EMT-6 tumor model, being both under the detection limits. Despite having a comparable excretion pathway, the disulfonated analogue showed an increased uptake in tumors, thus providing sufficient contrast for PET imaging.(199)
Scheme 2
Scheme 2. Synthesis of 64Cu-Labeled Phthalocyanines(200)
With imaging and treatment in mind, Liu and MacDonald have looked into the synthesis and evaluation of radiolabeled porphysomes. These nanoparticle platforms have been used as drug delivery vehicles.(98) As opposed to standard NPs, porphysomes do not require functionalization of the nanoparticle surface with metal radioisotope chelators.(98) Benzoporphyrin derivative monoacid (BPD-MA) was demonstrated to be a potent photosensitizer both in vitro and in vivo, as well as in clinical trials.(201) However, as many porphyrins exhibit a high level of lipophilicity, including BPD-MA, they have a tendency to aggregate in aqueous solution, therefore, limiting its bioavailability.(37) To circumvent this problem, porphyrins have been incorporated into liposomes for improved delivery, solubility, and efficacy.
Verteporfin, for example, has been utilized in clinical preliminaries and endorsed for clinical use, showing how liposomes have been considered as good delivery frameworks and as a feasible choice for the improvement of hydrophobic PSs.(202) A few authors extended the capacity of porphysomes by investigating the inherent capacity of the porphyrin–lipid conjugates to form steady, high-affinity complexes with copper-64, which has good attributes for nanoparticle tracking through positron emission tomography (PET).
Shi et al. prepared [64Cu]-Cu(II)-labeled pyropheophorbide-α (a near-infrared fluorescent porphyrin) derivatives coupled to folic acid for improved folate receptor interceded take-up in the tumor, opting to utilize the porphyrin element in a chelating role.(192) The porphysomes, composed of lipid functionalized porphyrin units, have been labeled specifically with copper-64 with a radiochemical load of 98%. The [64Cu]Cu(II)-labeled porphyrin units contribute to <5% of the porphysome molecular weight, unaffecting the nanoparticle size and photonic properties. The tumor uptake of the [64Cu]Cu(II)-porphysomes was evaluated at 24 h postinjection by PET/CT (Figure 13A) and fluorescence imaging (Figure 13B,C).
Figure 13
Figure 13. In vivo multimodal imaging of [64Cu]-Cu(II)-porphysomes in an orthotropic prostate cancer model.(192)
3.3. Combination of PET/SPECT and Optical Imaging toward Multimodal Theranostic Agents
The different techniques used for imaging cancers are stand-alone techniques, and it becomes imperative to have multimodal probes, in order to progress in cancer treatments.(203−205) At the moment, our current imaging modalities are limited in what they can perform individually,(206) but by combining different techniques, new achievements are expected. In principle, multimodal imaging agents can combine magnetic resonance imaging (MRI),(175,207) fluorescence imaging,(207−209) computed tomography (CT),(175,210) positron emission tomography (PET),(208,210) and single-photon emission computed tomography (SPECT).(175,203)
Recently, the feasibility of using multimodal agents has been verified in multiple in vitro and in vivo models.(211,212) A series of multimodal probes, with magnetic elements, such as iron oxide,(213,214) or Gd(III)-based chelates,(215,216) were coupled to PS. These studies demonstrate a remarkable potential for image-guided cancer therapy. However, such hybrid materials have limited applications since they are difficult to synthesize and produce in large quantities.(210) Therefore, the extended clinical use of theranostic agents will require affordable and easy-to-make derivatives. Not all multimodality combinations are useful, but certain imaging combinations are more attractive because some possess synergistic properties, like the combination of optical fluorescence imaging and PET (OFI/PET).
As previously discussed, fluorescence is an inexpensive modality. It is easy to operate; it possesses multiplexing capacity and high spatial resolution at histologic or superficial levels. On the other hand, PET shows quantitative, noninvasive, and extremely sensitive in vivo imaging without depth restraint.(217,218) The molar sensitivity of OFI and PET are relatively equal and both excellent; therefore, they can be used at nontoxic tracer quantities.(217) Fluorescence contrast imaging shows a better spatial resolution than PET at the histologic and superficial levels.(219) Moreover, fluorescence probes are stable, unlike PET probes, which rapidly decay. PET, on the other hand, has a superior resolution to fluorescence imaging through deep tissues. Therefore, the OFI/PET dual modality is a promising combination in clinical preoperative PET imaging and intraoperative optical imaging-guided surgery or PDT. Among dual-modality OFI/PET probes, those containing NIR dye and especially those based on cyanine-based NIR organic dyes (Figure 14), are of particular interest due to optimal tissue penetration.(220)
Figure 14
Figure 14. Structures of Cyanine-Based NIR dyes.
Not only NIR dyes should be considered, those emitting in the visible region are also suitable, as fluorescence imaging can be partially compensated by PET. Similarly, dual-modality OFI/SPECT combines SPECT’s depth penetration, high sensitivity, and quantitative signals with the already mentioned advantages of OFI. The design remains very similar; however, γ-emitting radioisotopes such as technetium-99m and indium-111 are used. Indium-111 is the most common SPECT radionucleus, and it is often coupled to cyanine-based NIR fluorescent groups. Moreover, to increase the response for cancerous tissues, targeting groups are generally employed.
In view of generating a “trifunctional agent” for double-imaging (PET and fluorescence) and PDT treatment, Pandey et al. have modified the tumor-avid porphyrin (pyropheophorbide a), and reported the synthesis of a 124I-labeled PS with high (>95%) radioactive specificity.(199) The half-lifetime of the nuclide allows us to perform the synthesis of the labeled PS and to accumulate in the target tissues after injection. They were the first to demonstrate that selective accumulation of porphyrin-based trifunctional agents to tumors can be achieved, thus confirming that using a single agent for imaging (PET and optical) and therapy is a promising avenue. In contrast to other studies, the different techniques are noninvasive, and the use of a single agent limits inconsistencies in the pharmacokinetic and pharmacodynamic patterns of the compound at all stages.
Another example of multiple-modality imaging with a known photosensitizer as the fluorescence probe was published by Cheng and co-workers.(221) A PEG-Ce6 nanomicelle was successfully prepared and used for OFI/PET dual-modal image-guided photodynamic cancer therapy. The presence of chlorin e6 molecules allows the PEG-Ce6 nanomicelles to work as a chelating agent for [64Cu]Cu2+. After internalization, PDT was carried out in vivo at a low irradiation rate, showing an excellent therapeutic effect on tumors. They were able to elaborate a simple approach to synthesize biocompatible multifunctional PEG-Ce6-based theranostic agents with the right properties for multimodality imaging-guided tumor therapy. The size and shape of nanoparticles and nanomicelles ensure high tumor uptake in vivo and partial renal clearance. These results might improve future applications and end up in clinical trials for these theranostic agents. In addition, these PEG-Ce6 nanomicelles can chelate other metals (Mn2+ or Gd3+) for additional imaging modalities, thus providing high-resolution imaging for anatomical information. Combining PET/OFI/MRI can be a winning combination since it can gather crucial information. The high sensitivity of the imaging techniques and excellent resolution of the images should help physicians to design better therapeutic approaches for cancer treatments.(221) In this regard, Li et al. acknowledged that nanotechnology is an ideal platform to combine different imaging agents into hybrid materials. Moreover, they can have a tremendous impact on tumor diagnoses.(222) Representative nanoparticles for their use as multimodal agents and their biomedical applications can be found in Table 4.
Table 4. Representative Nanoparticles and their Biomedical Applications(90,291)
| type of nanoparticle | possible surface modifications | imaging modality applicable | possible therapeutic strategies | synthetic protocol |
|---|---|---|---|---|
| quantum dots | lipids, polymer, targeting ligands or biomolecules | optical | PDT | colloidal synthesis, self-assembly, viral assembly |
| dendrimer | charge, polymer, targeting ligands, or biomolecules | MRI, optical | drug and gene delivery | organic chemistry techniques |
| liposome | charge, polymer, targeting ligands or biomolecules, viral protein coating | MRI, optical, radionuclide imaging | drug, gene and protein delivery, PDT | emulsion, polymerization |
| gold nanoparticle | lipids, polymeric shell, targeting ligands, or biomolecules | CT, optical | drug delivery, PTT | biological reduction, colloidal synthesis, vapor precipitation |
| carbon nanotube | polymeric shell, targeting ligands or biomolecules | MRI, optical, radionuclide imaging | drug delivery, PTT | arc discharge, laser ablation, vapor precipitation |
| mircrobubble | polymeric shell, targeting ligands or biomolecules | ultrasound | drug, gene and protein delivery | emulsion, layer-by-layer fabrication, polymerization |
| iron oxide | charge, dextran, lipids, polymer, targeting ligands or biomolecules | MRI | siRNA delivery, PT | coprecipitation, decomposition, microemulsion, sol–gel, thermal |
| micelle | charge, polymer, targeting ligands or biomolecules | MRI, optical, radionuclide imaging | drug and gene delivery | microemulsion |
| silica nanoparticle | charge, polymer, targeting ligands or biomolecules | MRI, optical | drug and gene delivery | chemical polymerization, microemulsion |
Nanoparticles are behaving differently from single molecules or bulk particles. They have properties of their own, and this can be nicely exploited in medicine. For example, nanoparticles tend to accumulate and internalize selectively to cells, being transported across membranes via transcytosis.(223) Furthermore, structural modifications of nanoparticles can be performed chemically, thus modifying not only their properties but also their biocompatibility.(224) However, to develop nanoparticles with multimodal imaging or therapeutic capacity, multiple factors need to be considered, such as toxicity, interaction with metabolites, biocompatibility, and biodegradability.(224)
Among multimodal techniques associated with nanoparticles, those involving SPECT/CT are the most common. For example, a liposomal nanocarrier incorporating technetium-99 has been developed for SPECT/CT imaging.(225) The imaging probe was used to visualize the amount of drug delivered to tumors. In addition, the therapeutic effects of this probe were determined using different tools. These probes can gather multiple information from different imaging modalities without having to inject other substances.
Overall, multimodal imaging agents should have a low toxicity and/or high biodegradability. They should have a high selectivity to target the disease. These characteristics would allow us to evaluate the efficacy of specific targeting and to determine the toxicity caused by the off-target accumulation of the multimodal imaging agent. On the other hand, there is a need to develop more efficient nanocarriers for controlling the external release of nanoparticles. Only then can this approach start to be considered for effective clinical translation and accurate diagnosis.
4. Imaging Hypoxia in PDT
ARTICLE SECTIONS
One of the major drawbacks in PDT is the increased oxygen needs. As mentioned earlier, oxygen consumption is predominant through the active mechanism of PDT, resulting in aggravate further the hypoxic conditions in tumors. It is well-known nowadays that tumor hypoxia can be linked to tumor aggressiveness, metastatic spread, poor tumor control, increased level of recurrence, and unfortunate therapeutic outcomes, mainly due to radiation and chemotherapy resistance.(10,226−230) Taking into account the variability of O2 concentrations within tumors and even tumor regions, it is quite undeniable that O2 concentrations will have an impact on PDT treatments.(231) Regrettably, solid tumors are known to show acute hypoxia due to a series of abnormal physiological variations in the tumor microenvironment including uncontrollable tumor cell proliferation, an irregular vascular system, and a deteriorating microenvironment.(232,233) The degree of hypoxia is, therefore, directly linked to cancer treatment effectiveness.(234,235)
An increasing interest in developing methods to measure tumor hypoxia has, therefore, been raised. These techniques can either be invasive (e.g., polarographic O2 sensor) or noninvasive (e.g., molecular imaging), and they both aim at measuring the oxygen level within the tumors. Medicinal imaging (optical, MRI, PET, and SPECT) has become a useful tool to characterize the variability and magnitude of hypoxia within tumors and to help the physicians’ decisions.(236) Optical imaging techniques assess the optical absorption, scattering, and fluorescence in tissues.(237) MRI techniques, based on contrast agents (endogenous or exogenous), embrace techniques such as electron paramagnetic resonance (EPR),(238) dynamic contrast MRI (DCE-MRI), magnetic resonance spectroscopy (MRS),(239) and blood oxygen-dependent level (BOLD) imaging.(240,241) However, undoubtedly, one of the most extensively investigated imaging modality toward hypoxia imaging is PET due to the various advantages discussed in the previous section and to the development of hypoxia-specific radiolabeled agents.(242−244) Since the very early stages of hypoxia research, it has been revealed that several nitroimidazoles and thiosemicarbasides can directly and reproducibly identify the absence of oxygen.(245)
In 1981, Chapman et al. pioneered the use of nitroimidazole derivatives and molecular imaging techniques to evaluate the degree of hypoxia in tumors.(237) These compounds are particularly interesting because the oxygen-binding affinity to nitroimidazoles is directly linked to cell retention and O2 concentration (Scheme 3).(246) Following this study, hypoxia-specific agents targeting intracellular macromolecules have made possible the widespread use of PET for imaging hypoxia.
Scheme 3
Scheme 3. Mechanism of Nitroimidazole Derivatives in Hypoxic Cells
Nowadays, copper-based complexes incorporating bis(thiosemicarbazone) ligands have become the most effective class of compounds for imaging diagnostics of hypoxic tumors. The pharmacological activity and theranostic properties of these complexes have allowed the determination of the origin of hypoxia and how it is involved in tumors and heart diseases. The mechanisms by which these copper complexes (CuATSM) are hypoxia selective seem to be associated with metal coordination. The hypoxia selectivity involves intricate intracellular reduction–oxidation processes, leading to Cu(I) species, which are free from the chelated complex via redox reactions (Figure 15). In hypoxic environments, Cu(II) species are easily reduced to Cu(I) derivatives, and upon decomplexation, the Cu(I) can interact with biomolecules.(247) This phenomenon is essential for delivering free copper to cells. However, it does not guarantee a selective uptake.(248) Therefore, to increase selectivity, bis(thiosemicarbazonato) complexes as well as thiosemicarbazide analogues have been modified to better target tumors, and their responses in vitro have been explored worldwide.(247,249−251)
Figure 15
Figure 15. Proposed mechanism of hypoxic selectivity for [64Cu]CuATSM.(247,251,252)
To date, only a few PET agents have been evaluated in clinical trials: [18F]-fluoromisonidazole ([18F]FMISO),(253,254) [18F]-fluoroazomycin arabinoside ([18F]FAZA),(255) and [64Cu]copper-diacetyl-bis(N(4)-methylthiosemicarbazonato),(248,249) being the most promising ones. Although [18F]FMISO is consensually known as the gold standard in clinical research for hypoxia measurement, it is considered to have low-specific tissue accumulation resulting in limited imaging contrast of hypoxic tissues compared to normoxic areas, slow nonhypoxic cellular wash out, and no specific time for image acquisition.(256,257) [18F]FAZA was developed along with the second-generation 2-nitroimidazoles, and while it has been denoted that it overcomes most of [18F]FMISO’s limitations, its intertumoral activity is lower.(254,258)
On the other side, studies suggest that [64Cu]Cu(ATSM) occasionally possesses better properties,(259,260) due to its capacity to enter hypoxic cells and localize in tissues with low O2 concentrations.(261) However, its selectivity seems to be related to the intracellular redox potential (Figure 16).(262,263) Subsequently, regardless of the collection of different tracers that are currently used for hypoxia tracing, none of them provide reproducibility across variant hypoxia subtypes, and new ones need to be developed in order to raise the sensitivity, the selectivity, and the resolution of the imaging studies.
Figure 16
Figure 16. Studies showing the relationships between the retention of [18F]FMISO and [64Cu]Cu(ATSM) and hypoxia. (a) Coregistration of the [18F]FMISO PET signal (2 h postinjection) with the [64Cu]Cu(ATSM) PET signal (3 or 24 h postinjection. (b) [18F]FMISO and [64Cu]Cu(ATSM) uptake was evaluated at 2 and 24 h after radiotracer injection, respectively.(260)
Lately, gallium-68 (∼68 min) is one of the radionuclides that has been commonly applied as a probe. These systems usually contain a nitroimidazole or a macrocyclic ligand, which is able to complex gallium-68 (for example, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid or 1,4,7-triazacyclononane-1,4-diacetic acid, generally alluded to as DOTA and NOTA). A variety of studies have shown improved clearance and successful hypoxia imaging compared to [18F]FMISO. Recent studies have also demonstrated an affinity for the (HIF)-1 regulated carbonic anhydrase-IX receptor (CA-IX), a renowned endogenous marker of hypoxia.(264)
Hypoxia-responsive domains have been reported, and functional groups, such as nitro, quinone, transition metals, aliphatic, and aromatic N-oxides, have been identified for chemo-drug release. Such derivatives have been studied by different groups and recently added to the design of carriers for PSs and for anticancer drugs. These systems have led to the development of hypoxia-responsive nanoplatfom domains.(265,266) For instance, light-activatable nanoparticles (NPs) with nitroimidazole groups was developed by Lin et al. to selectively release drugs in hypoxic cells.(267) Furthermore, Gu’s team has reported a 2-nitroimidazole (NI) conjugate linked to the dithiophene-benzotriazole polymer (NI-CP), which can encapsulate doxorubicin (DOX) via a double emulsion method, thus forming a DOX decorated polymer (DOX/NI-CP).(268) Near-infrared (NIR) light irradiation was performed after accumulation in the tumor region, showing a good production of ROS despite the hypoxic conditions. Moreover, the tumor hypoxia aggravated by the photodynamic reaction facilitated the cargo release, which turns this procedure into a self-feedback process, leading to selective drug release and an excellent therapeutic effect. This study suggests that the introduction of PSs in hypoxia-sensitive delivery carriers offers spatiotemporal control over the drug released, thus providing another type of theranostic agent.(269)
Moreover, it has been established that PDT planning might be facilitated by molecular imaging through the estimation of the biodistribution of the PS in tumors. However, the concentration of oxygen remains crucial for PDT efficacy, and the role of imaging in this regard is often overlooked. Increasing intratumoral blood flow, using oxygen carriers, generating oxygen in situ, and targeting hypoxia-induced factors are some of the strategies that have, up to now, been developed to overcome tumor hypoxia. From all techniques, one, in particular, has stood out. This technique takes into consideration the existence of endogenous hydrogen peroxide (H2O2), which is naturally produced in cancerous cells. This approach utilizes H2O2 catalysts, such as catalase (CAT), to decompose H2O2 into O2. Though, as an exogenous enzyme, the protease induced degradation as well as the immunogenicity of CAT, two non-negligible factors that need to be considered.(270−273)
Some authors have looked into the possibility of taking advantages of the porphyrin structure of THPP to coordinate metal ions and have come up with catalase-entrapped nanocapsules (CAT-THPP-PEG). To increase solubility, the nanocapsules are functionalized with short polyethylene glycol (PEG) chains. The enzymatic activity and stability of catalase are ensured by the CAT-THPP-PEG nanoparticles, which, after labeling with technetium-99m, can be traced by in vivo SPECT imaging. These nanoparticles have prolonged blood circulation and show efficient tumor retention after intravenous (iv) injection, and once located in the tumor, the catalytic activity is regained, transforming H2O2 to O2. These very interesting therapeutic responses were associated with the nature of the PS (THPP) and tumor hypoxia. Moreover, in mouse tumor models, reduced immunogenicity was observed as compared to free catalase. The authors, therefore, presented an easy approach for the preparation of a unique type of enzyme entrapped theranostic nanocapsules, using PS as linkers. This, ultimately, allows for enhanced cancer therapy by modulation of tumor hypoxia via nanoparticle functionalization. The enzyme stability and reduced immunogenicity, which also enhance PDT, enable in vivo SPECT imaging to become an attractive cancer theranostic nanoscale platform.
5. Discussion and Perspectives
ARTICLE SECTIONS
In general, standard medical protocols analyze a disease or disorder, determine its characteristics, and then apply treatments. A similar strategy is employed by the researcher when developing new drugs or new modalities of treatment.(274) Despite the predominance of this old-fashioned strategy, studies suggest that, for some diseases, another approach should be taken. Most of the modern diseases are heterogeneous in their behavior and appearance.(274) For instance, with a cancer patient, the first step is to identify the phenotype, then the heterogeneity is assessed, and finally, the stage in which the cancer has evolved is determined.(89,275) According to the stage and the characteristic of the cancer, the patient will receive a specific modality of treatment, so two patients with a similar disease may end up with different treatments.(17) The “one size fits all” approach that has been preconized for many years is not viable with cancers; the more we learn about the disease, the better we understand that a different approach is needed for developing successful treatment against cancer.(276)
The preferential localization of porphyrins in tumors, their ability to produce reactive oxygen species upon light activation, and their low toxicity have made them perfect molecules for photodynamic therapy. Moreover, the photophysical properties of porphyrins and the possibility to bind metal ions provide a unique platform for developing imaging agents. An ideal imaging agent is harmless to the body, and it possesses a fluorescence intensity above the cellular autofluorescence. These characteristics have been incorporated in recently synthesized porphyrins or porphyrin conjugates.(277) It is also important to note that porphyrin analogues, such as phthalocyanines, chlorins, and bacteriochlorins, are also good candidates for imaging, and several reviews have been written on the subject.(278,279) Although porphyrin analogues show similar behaviors and similar applications, they are often studied separately. Metalloporphyrin is another type of porphyrin derivatives that can be used as imaging agents. The introduction of metal ions in the porphyrin core modifies the photophysical property of porphyrins, and accordingly, it can improve the phototherapeutic efficacy, provide MRI contrast, and enhance Raman imaging.(280) In conclusion, metalloporphyrins own all of the essential characteristics of becoming theranostic agents.
There are, however, two main limitations of porphyrin-based imaging agents in therapy, and they come down to the synthesis and the aggregation of porphyrins. The principal strategy for the synthesis of these compounds is based on the condensation of mixed aldehydes resulting in a complex mixture of porphyrin derivatives, which are often difficult to purify and to isolate. Then, despite having pure molecules, the planar aromatic structure of porphyrins increases the probability of aggregation, a problem encountered by most researchers in the field.(281) Aggregation is not only a problem when it comes to therapy because it is usually related to low solubility, which, in the case of PDT, means worse pharmacokinetic profiles but also in imaging because aggregation usually translates into changes in the absorption spectra.(282) In this way, having lower Soret bands would damage the pharmacodynamics of PDT as well as the imaging due to their decreased fluorescence. Therefore, many researchers have turned, as previously explained, to the solution of these problems by conjugation with nanostructures, which promise to help overcome these challenges.
On the other hand, more specific and individualized modalities of treatment are needed.(283) Diagnostic tools are vital for determining the progress of a disease in a patient, and combining diagnostic and therapeutic applications in a single molecule can, in principle, provide personalized treatments.(226) Having a single platform(99) will help doctors to apply the best treatment to individuals and, by doing so, will reduce side effects and other undesirable outcomes.(284)
The advent of novel drug delivery technologies is essentially driven by the observation that many therapeutic agents are not able to localize preferentially in target tissues and/or because of their lack of selectivity against diseased cells. Commonly, a preclinical biodistribution study leads to the quantification of the drug over time in tissues/organs. Generally, these studies are carried out ex vivo through time-consuming methods that required the sacrifice of many animals. These days, this can be done in vivo and in real time using imaging methodologies and tailored imaging probes. In a typical nanomedicine approach, the nanocarrier is loaded with both the drug and the imaging agent, an agent that can be detected by the corresponding imaging technique. Due to the good quantification properties and outstanding detection sensitivity, radioisotopes that have been broadly utilized for ex vivo biodistribution studies may have an interesting potential for in vivo applications. Kopelman et al. gave an example of such systems, in which an intricate mixture of porphyrin oligomers (porfimer sodium) and MRI contrasting agents were trapped together in a nanoparticle (Figure 17).(172) In these systems, the nanoparticles were functionalized at the surface with RGD targeting sequences and PEG for immune cloaking. Then, after delivery to tumors in rats, the photosensitizers were activated by light. The results show a complete necrosis of 9 L gliosarcoma tumors in rats within 5 min.(172)
Figure 17
Figure 17. Schematic PAA core matrix nanoplatform with photodynamic dye, MRI contrast agent, polyethylene glycol (PEG) loading, and molecular targeting groups.(172)
As it was mentioned earlier, the effectiveness of photoinactivation can be affected due to PS aggregation.(285) Taking this into consideration, several studies have looked at different carriers to avoid aggregation, to stop degradation, and to increase uptake. For example, silica-based NPs (SiNPs) have been loaded with PSs.(286−288) In the clinical field, SiNPs are used as cell markers,(289−291) drug and gene delivery platforms,(291,292) enzyme adsorption, and immobilization agents,(293) and they are able to internalize cells.(289−291) Therefore, it made sense for them to be investigated for PDT applications. Synthetically modified SiNPs, such as ORMOSIL, mesoporous silica NPs (MSiNP), and hollow SiNPs (HSiNP), are frequently used in the clinic. These SiNPs are particularly appropriate for PDT as they show chemical inertness, and they are structurally stable. At the same time, they are resistant to pH variations and do not absorb light. However, perhaps most importantly, the functionalization of SiNPs ensures a monomeric environment to all PSs, thus avoiding aggregation phenomena. Moreover, singlet oxygen can travel through the SiNP shell.(294) Finally, the functionalization of SiNPs remains relatively easy, and the surface of SiNPs can accommodate all kinds of functional groups, including PEGs, antibodies, peptides, glycosides, and several other biomolecules.(286,295,296)
ORMOSIL functionalized NPs have shown great promises for PDT applications.(286) They have been widely studied because of their hydrophobic/hydrophilic tunability, which can ease the solubility of PSs. Accordingly, Ohulchanskyy et al. have prepared ORMOSIL NP derivatives with covalently bound PSs. The covalent attachment of the PS increases the stability and avoids leaching of the PS before reaching its target.(297) Among different systems, the iodobenzylpyropheophorbide derivative (Figure 18) was synthesized to initiate a coprecipitation reaction, thus facilitating purification and isolation of the compound. These ORMOSIL and ORMOSIL-PS conjugates were evaluated on two tumor cell lines, Colon-26 and RIF-1. The study shows an excellent uptake by cells and that the photophysical properties of the PSs are preserved. Indeed, upon light activation, the phototoxicity of the PSs was comparable to that of the PS alone. Moreover, the authors highlighted the possibility of replacing the natural iodine of iodobenzylpyropheophorbide with a different isotope (e.g., I-124, I-125, etc.). This modification implies that the same systems can be used as contrast agents (PET/SPECT), while still having PDT effect, thus becoming theranostic agents.(297) A similar observation was made by other groups, on systems involving other PSs covalently linked or encapsulated in ORMOSIL NPs.(298)
Figure 18
Figure 18. Iodobenzylpyropheophorbide precursor for functionalization to ORMOSIL NPs.
Metal NPs are another category of NPs commonly used in PDT. Among metal-based NPs, gold NPs (AuNPs) are particularly attractive, due to their distinctive properties, which make them perfect candidates for labeling, delivery, heating, imaging, and sensing applications.(299−301) Mostly linked to their biocompatibility, precise structure, limited surface, and optical properties, gold NPs have received a great deal of attention in PDT.(302−304) While the introduction of specific groups (thiol, amino, cyano) confer the colloidal stability,(221) the functionalization of gold NPs with lipids, proteins, oligonucleotides, or PSs can improve their biological properties (targeting, stability, selectivity).(300) In fact, the conjugation of PSs on the surface of AuNPs may produce an enhanced electromagnetic field as a result of localized surface plasmon resonance of AuNPs upon light activation and, consequently, an increase the PDT efficacy (Figure 19). This phenomenon will enhance the PS excitation rate, increase ROS production, and, ultimately, will generate an improved PDT agent.(301,302)
Figure 19
Figure 19. Cartoon illustrating the surface plasmon resonance phenomena on gold NPs.
The use of hydrophilic AuNPs as a platform to prepare multimodal systems was recently published by Penon et al.(305) The multifunctional AuNPs (PS-AuNPs-PEG-Ab) show porphyrins and PEG chains connected to an anti-erbB2 antibody. The antibody aims to target overexpressed erbB2 receptors, which are commonly found on the membrane of SK-BR-3 breast cancer cells. The different components are attached to the AuNPs via thiol groups, which have a high chemical affinity for AuNPs. These functionalized NPs are photoactive, producing 1O2 and killing cells under PDT conditions. It was also demonstrated that the PS-AuNP-PEG-Ab conjugate accumulates in cells, and upon photoactivation, damage to membranes and modification to cellular morphology were detected.(305)
Like metal-based nanoparticles, nanotheranostic particles involving PDT can destroy their targets. However, to be effective, nanotheranostic particles need to reach their target, to avoid off-target phototoxicity. Therefore, it is important to monitor the localization of these particles in real time, in order to minimize side effects linked to the generation of reactive oxygen species outside the tumors.
Luckily, most photosensitizers used for PDT are also fluorescent molecules, a useful property that can be employed to localize the photosensitizer. Fluorescence spectroscopy is cheap to operate, it shows outstanding resolution in the appropriate spectral region, and it can be used in parallel to radioisotopes (PET and SPECT), thus being perfectly compatible with other techniques.(306,307) Photons released by naturally fluorescent biomolecules or from externally administered fluorescent probes can be used for imaging. However, some limitations are associated with fluorescence, including poor tissue penetration, high noise, and background from tissue scattering of photons in the visible region, autofluorescence, light absorption by proteins, and interference from water molecules.(99) Nevertheless, NIR activation can overcome these limitations in that region: tissue penetration of light is up to several centimeters, a low autofluorescence is observed, and tissue scattering is reduced to a minimum.(308,309)
Selectivity and targeting strategies are keys for fluorescence imaging and PDT. This can be achieved by passive transport, which implies the use of large molecules, such as nanoparticles. The particular size of nanoparticles increases their accumulation in tumors, and after internalization, the particles are retained (EPR effect). Peng et al. have developed multifunctional polymeric nanoparticles loaded with IR-780, which provide both NIR fluorescent dyes and photosensitizers in a large particle.(310) These micellar nanoparticles confirm that passive targeting can be accomplished with nanoparticles.
Using similar concepts, Tsai and co-workers studied the accumulation in cells of nanoparticles decorated with the photosensitizer PPIX.(311,312) They found that the pH-sensitive particles were delivering PPIX in the nucleus, while non-pH-sensitive nanoparticles were delivering PPIX in lysosomes.(313) In mice bearing A549 xenografts, the different accumulation was nicely linked to the biological activity. Indeed, the pH-sensitive nanoparticles have a stronger inhibition on tumor growth, suggesting that the localization of the photosensitizer in cells can strongly affect PDT.
Like PPIX, chlorin e6 (Ce6) is another popular photosensitizer used as a theranostic agent.(314−316) Lee et al. have developed glycol chitosan nanoparticles to transport Ce6 to cells.(317) Two transport systems were evaluated: one involving physical encapsulation and the other involving covalently linked Ce6 nanoparticles. The conjugated system showed a longer circulation time, a better-controlled release of Ce6, and a higher accumulation of the PS to tumors. The increased accumulation in tumors of mice bearing HT-29 human colon adenocarcinoma was established by NIR imaging. Then, PDT treatments on the same tumors showed severe necrosis and mass reduction of tumors.
Phthalocyanines (Pc) are also a class of molecules with significant potential as theranostic agents, given the strong absorption within the NIR window. For example, a fluorescent Pc-loaded graphene nanoplatform was used as an imaging and PDT agent on ovarian cancer cells.(318) Similarly, a biocompatible carbon nanodot loaded with zinc Pc was used for the same modalities (imaging and PDT) on HeLa cells, as well as on animal models.(319) Both examples confirm the usefulness of passive transport in view to target tumors for PDT and fluorescence imaging.
A second strategy to target tumors and add selectivity to PDT/imaging agents implies the development of activatable multifunctional agents, which can become active after responding to a biological or physical stimulus.(28) The activation can be triggered artificially (exogenous stimuli) by applying, for example, a magnetic/electrical field, ultrasound, or light. On the other hand, the activation can be triggered biologically, by physiological conditions associated with cancer (endogenous stimuli), such as the temperature, pH, or enzymatic activity.(152,320−322) Among these endogenous stimuli, pH is probably one of the most attractive targets, as tumors tend to have a mildly acidic pH.(173) Accordingly, charge-switching nanoparticles have been designed to react under acidic conditions (Figure 20). In such system, the positively charged region of the compound interacts strongly with negatively charged particles, especially those located in membranes, thus overall increasing cellular uptake.(315)
Figure 20
Figure 20. Mechanism of an activatable peptidic zipper-based PS.
Enzymes such as matrix metalloprotease-2 that are overexpressed in tumor cells can be targeted by activatable nanoparticles.(323) Likewise, a theranostic agent with double targeting possibilities can, for example, be fluorescent and phototoxic only after being released by tumor-associated lysosomal enzyme cathepsin B. This is particularly attractive for targeting folate receptor-positive cancer cells.(324) This strategy focuses on selectivity and specificity for malignant cells, using targeted moieties that can aim specific receptors found on the surface of biomolecules and inside cells. One frequently mentioned group is the RGD peptide (tripeptide Arg-Gly-Asp), which can target the integrin avb3 receptors that are overexpressed in several tumor types. RGD conjugates loaded in ICG nanoparticles showed promises for FGS in liver resection.(221) Conjugation of (i) RGD peptides for improved tumor targeting, (ii) temoporfin as a photosensitizer, and (iii) with fluorescent dye molecules for improved contrast has been performed.(325) An in vivo study has confirmed the dual modalities of these systems, fluorescence imaging and PDT.
Folic acid (FA) is another functional group that can be used to target specific receptors. Folate receptors are upregulated in ovarian, lung, brain, and breast cancers, thus making folate conjugates good candidates for increasing selectivity.(326) Wang et al. reported a nanoparticle that incorporates fluorescence imaging, PDT, and FA targeting ability.(327) Later on, a highly biocompatible carbon nanodot was synthesized, which incorporates the same modalities. Biological studies showed that the functionalized carbon nanodot increases fluorescence and has PDT effects in vitro and in mice.(319) More recently, FA-coupled nanoprobes loaded with Ce6 were synthesized, and after a series of in vitro and in vivo experiments to access specificity, efficacy, and safety, the multifunctional theranostic agent ability was demonstrated.
Radionuclide imaging is another strategy that combines high sensitivity and unlimited tissue penetration. It can be associated with imaging to monitor disease development. Usually, the half-life of the selected PET isotope matches the time necessary for imaging,(328,329) with the necessity of producing a high signal-to-background ratio at a target localization. For tumor imaging, copper-64 or zirconium-89 are normally used with systemic injection of an intact antibody to maximize the tumor-to-background ratio. Fluorine-18 is also a good radioisotope, which is already used in the clinic ([18F]FDG). However, 18F radiochemistry can be hard to manipulate at the radiochemical level, and 18F radiochemistry involved a covalent bond.(330−333) DOTA, on the other hand, involves coordination chemistry, and it is quite easy to use the same platform for different radionuclides and different imaging techniques, for example, copper-64 and gallium-68 for PET, indium-111 for SPECT, and yttrium-90 for radiotherapy. The versatility of DOTA provides an ideal system, where different imaging techniques can be applied to a single platform.
Another significant consideration when selecting a PET radionuclide is the time frame associated with the targeted biological event. In other words, the half-life of the positron-emitting radionuclide must fit with the biological event; otherwise, the results may be misleading and the imaging may not provide answers. For example, copper-64 possesses a half-life of 12.7 h, ideal for tracking monoclonal antibodies over a period of 48 h, while fluoride-18 with a half-life of 110 min can be used to trace fast clearance molecules.(334) Therefore, radioisotopes such as carbon-11, fluoride-18, copper-64, bromide-76, technetium-99m, indium-111, and yttrium-90 have been utilized along with various copolymers, in view to develop robust nanodelivery systems.(335−337)
If we take into consideration the already mentioned impact of hypoxia on tumor progression, metastatic spread, absence of tumor control, amplified recurrence phenomena, and poor therapeutic outcome, then imaging hypoxia is a step forward. As opposed to other noninvasive techniques, PET imaging offers specificity for the detection of hypoxic tissues. In this regard, the first compounds to address the imaging of hypoxia tissues were developed in the early 1980s.(338) They consist of 2-nitroimidazole derivatives linked to multiple PET tracers (Figure 21).
Figure 21
Figure 21. Structures of known [18F]-based 2-nitroimidazole derivatives.
The main idea behind these [18F]-based 2-nitroimidazole derivatives is to have a stable compound showing high specificity for imaging hypoxia without the inconsistent correlation that is often associated with other imaging techniques like PET with [18F]-fluorodeoxyglucose ([18F]FDG). The most common PET tracer for hypoxia imaging is the fluorinated nitroimidazole derivative [18F]-fluoromisonidazole ([18F]FMISO).(338,339) Like other compounds in the nitroimidazole family, [18F]FMISO can diffuse passively through cell membranes due to its lipophilicity. Then, after internalization, the compound is reduced into R-NO2 radicals by the nitroreductase enzyme (NTR). This process remains reversible, meaning the tracer will only stay in the cell under hypoxic conditions; otherwise, in the presence of oxygen, the tracer is released. As mentioned, in the absence of oxygen (pO2 < 10 mmHg), the reduction process is much slower. Consequently, the increasing production of R-NHOH derivatives that bind directly to intracellular molecules ensures that the level of tracers inside cells is high.(340−343) However, the main drawbacks of [18F]FMISO include the fact that passive transport requires 2–4 h after intravenous injection for [18F]FMISO to accumulate to hypoxic tissues(344,345) and that, despite this uptake period, tracer accumulation remains low.(344,346)
Alternatively, among the non-nitroimidazole compounds, radioactive copper (copper-60, -61, -62, -64) labeled with diacetyl-bis(N4-methylthiosemicarbazone) [64Cu]CuATSM) is another promising PET radiopharmaceutical for hypoxia imaging. First studied in 1997, the compound has shown suitability for the detection of hypoxia in living tissues.(250) However, the mechanism of uptake remains unclear. Nevertheless, it is known that [64Cu]CuATSM is a neutral lipophilic molecule, which is easily crossing membranes by passive diffusion.(340) Fujibayashi et al. suggested that, after internalization, the accumulation in tumor cells mainly depends on the cytosolic/microsomal bioreduction process.(347) The bivalent [64Cu]Cu(II)-ATSM, once inside cells, undergoes a thiol reduction and is converted to the less stable Cu(I) complex [64Cu]Cu(I)-ATSM.(348) In hypoxic conditions, this complex is progressively dissociated into H2-ATSM and free Cu(I), which can rapidly coordinate to proteins.(250,347−349)
It is, therefore, plausible that copper itself plays a major role in the [64Cu]CuATSM entrapment. In order to verify this hypothesis, Hueting et al. analyzed the in vitro and in vivo distribution of [64Cu]CuATSM and [64Cu]CuOAc in animal models (EMT6 and CaNT).(248) The study shows that both copper tracers accumulate in similar fashion in tissues, confirming that copper metabolism takes part in the activity of [64Cu]CuATSM.
Hypoxia for cancer patients is very important, and the development of prognostic biomarkers for hypoxia can make a huge difference in the success or failure of a treatment. Additionally, identifying hypoxia in vivo without any intrusive intervention may facilitate its use in the clinic. Nonetheless, determining the best tracer for this purpose remains difficult. While some data suggest that [18F]FMISO is an excellent candidate, a suboptimal imaging limitation remains. On the other hand, high PET image quality favored the use of [64Cu]CuATSM. Besides, when directly compared to the principal 2-nitroimidazole family representative ([18F]FMISO), [64Cu]CuATSM uptake is significantly better in hypoxic tissues than in other areas, and it reaches its target more rapidly (10–15 min versus 2–4 h).(259) It is clear that these achievements are important and can potentially generate better theranostic-PDT agents.
Even though the outlook for imaging seems encouraging, obstacles remain high for commercial applications. In fact, both imaging agent development and standard drug discovery and development share much in common, especially those binding to a specific target in vivo. Both must overcome several challenges when it comes to factors such as target authentication, identification of the best possible candidate, showing high affinity and selectivity, as well as good clearance, and low toxicity.(350)
The impact of a therapeutic intervention is difficult to evaluate in cancer treatment, which makes the validation of molecular imaging biomarkers difficult when compared to existing surrogate markers. A quantitative assessment through imaging can help to determine the real impact of a new treatment (complete or partial response), and it can provide information on the progression of the disease.(351) PET/CT and other hybrid imaging modalities, by overlaying different images, allow the determination of the therapeutic effect with PET and the size of the tumor with CT.(352)
Another challenge is the need to understand the drug’s mechanism of action when integrating PET or SPECT into clinical research. For example, [18F]FDG PET may help to identify downstream effects at an early stage of cancer development, even before tumor shrinkage. Routine clinical use of [18F]FDG PET involves static imaging 2 h post-injection, which can be useful if we only want the localization of tumors and metastases. On the other hand, if we are intent to perform dynamic imaging, the recollection of PET data from the initial injection of [18F]FDG will give direct access to pharmacokinetics and pharmacodynamics information on the tracer, which can be very important for better understanding how drugs and therapies work in real time.(353) This example illustrates the careful planning and deep understanding that is required of all of the processes involved when trying to perform the imaging of cancer and how they can limit or help each other.
We can, by this, conclude that the similarities between the processes of developing therapeutic drugs and diagnostic agents make their simultaneous development into theranostic agents even more challenging. At the same time, technologies and development from one domain can accelerate the development processes of the other (PET microdosing, for example). Finally, the development of new drugs incorporating tracers and imaging biomarkers can also contribute to the emergence of theranostic agents.(350)
6. Our Contributions
ARTICLE SECTIONS
As it can be understood from this review, there is an urgent need for new drugs and practices to treat cancer. Photodynamic therapy (PDT) imposes itself as one of the most preponderant voices to answer this demand. With the combination of a photosensitizer, light, and oxygen, PDT achieves a unique selectivity by the production of localized reactive oxygen species inside tumor cells, which leads to their destruction with limited side effects.(354) Our approach aims to use cellulose nanocrystals to transport and deliver radiolabeled photoresponsive molecules to biological targets and create new theranostic agents.
In order to achieve our goal of using these cellulose-metal-porphyrin assemblies and to trace them using SPECT imaging, several steps have been taken so far. First, we have prepared and characterized CNCs(355) as well as photoresponsive molecules through stoichiometric quantities of aldehydes and pyrrole in propionic acid (Scheme 4).(356) Then metalla-assemblies were obtained using inorganic metalla-clips under a well-developed methodology.(357) The last step was to load these metalla-assemblies to nanocrystals by dissolution in methanol, adding them dropwise to the CNC solution and leaving it to react for 24 h.(355) Derivatives of the 5,10,15,20-tetra(4-pyridyl)-21H,23H-porphine were chosen as photoresponsive molecules, due to their ability to simultaneously be linked to the cellulose nanocrystals (CNC) and coordinated to ruthenium. Even though different grafting methods were explored, the best results were achieved through the covalent amide binding of the photosensitizer and the CNC.
Scheme 4
Scheme 4. Synthesis of Cellulose-Metallo-Porphyrin Theranostic Agents
Labeling of CNC with the nonradioactive metallic isotope has also been explored, and the radiolabeling experiments will follow shortly. A full set of in vitro assays with the nonradioactive derivatives will be performed to determine the IC50 and the influence of the cage and CNC to cells. Following the in vitro study, in vivo imaging will be conducted, and the data will be processed and statistically analyzed.
Our preliminary results are very promising regarding the synthesis of a multimodal agent that combines a photosensitizer for PDT treatment and a radioactive agent for imaging (before, during, and after the process), thus aiming to develop an innovative theranostic agent. The conjugation with cellulose nanocrystals and coordination to inorganic entities intend to ameliorate their delivery, solubility, and metabolism.
7. Conclusions
ARTICLE SECTIONS
The importance of PDT in the treatment of cancers as well as nononcological diseases is growing rapidly. However, despite increasing reports showing the benefits of PDT over traditional treatments, extensive use in the clinics remains to be seen. This limited utilization of PDT in the clinics is due to different factors, some linked to the pharmaceutical formulations of PDT agents (solubility, administration, aggregation, selectivity) and some to the technology involved (instrument, light source, etc.).
For more than 20 years, researchers have focused on developing safer and more effective PDT agents not only to cure cancers but also to be used in many other domains.(358) During that period, the clinical success of PDT for the treatment of head and neck cancers is undeniable, showing an increased survival rate of patients with such cancers, as well as an improved quality of life. Similarly, the cure of some early stage tumors, precancerous lesions, and nonmelanoma skin cancers has been enormously effective.(7) In addition, the association of PDT to NPs technology has offered new solutions and new perspectives to further develop the field of photodynamic therapy.
Photodynamic treatment (PDT) is and should be considered a therapy with promising outcomes for the treatment of different diseases, the most studied one being cancer. This treatment depends on the impacts of light conveyed to photosensitized cells. Therefore, adding molecular imaging to PDT treatment is crucial and keeps on expanding, from disease detection, treatment planning, to real-time monitoring and its outcome evaluation. While there has been impressive progress over the past decade, to be successful in the clinic, numerous technical difficulties must be investigated and ameliorated, for example, the requirement of imaging probes to precisely recognize the spatial and temporal occurrence of specific cell death processes. As cancer is proliferating fast, innovative diagnostic and therapeutic strategies are imperative for early detection and precision treatment. In addition, to optimize the therapeutic outcome of PDT, an evaluation of the local microenvironment before treatment is essential. For example, as photosensitizers (PSs) need oxygen to operate, the presence or absence of O2 is crucial for the production of toxic reactive oxygen species (ROS), according to PDT treatment. Therefore, without specific information on local O2 concentrations during PDT treatments, the effectiveness of treatments can fluctuate greatly. Moreover, due to O2 consumption during PDT treatments, the oxygen level needs to be continuously maintained to ensure efficacy. Thus, measuring O2 levels in real time during PDT treatments has become one of the main challenges for the future of PDT.
So far, multiple sensors have been used to monitor O2 concentrations in biological media, thus providing convenient imaging tools for refining cancer diagnosis and improving therapeutic efficiency. However, the combination of an imaging agent with a photosensitizer to generate a theranostic O2 sensory platform for image-guided PDT has been rarely reported.(359) In the clinic, PET imaging has become one of the most effective tools to visualize tumor hypoxia in patients. It has been used clinically on various cancer types with different radiotracers. It is now well-documented; PET imaging can increase treatment response and optimize radiotherapy plans. OFI and PET as double-modality contrasting agents have proven to be an excellent combination. The OFI/PET systems show low toxicity, and they possess high spatial and long temporal resolutions.(206)
In summary, multimodal imaging presents itself as a powerful tool to make an accurate picture of diseased sites. The accumulation and retention of nanoparticles in real time can be quantified by PET imaging, while OFI imaging can provide other information at a cellular/molecular level. Together, they can validate and optimize treatments without being too expensive. Therefore, the emergence of integrated diagnostic and therapeutic agents in a single system is a valuable strategy to develop new therapeutic combinations in PDT.
Author Information
ARTICLE SECTIONS
- Bruno Therrien - Institute of Chemistry, University of Neuchatel, Avenue de Bellevaux 51, CH-2000 Neuchatel, Switzerland;
http://orcid.org/0000-0002-0388-2745;
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
This project has received financial support from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 764837.
Biographies
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João C. S. Simões
João C. S. Simões was born in Coimbra, Portugal. He concluded his Bachelor’s in 2016 and Master’s in 2018, both at the University of Coimbra in Medicinal Chemistry. His Master’s thesis consisted of “Novel Ring-Fused Chlorins as Promising PDT Agents against Cancer”. Currently, he is an Early Stage Researcher within the POLYTHEA project, in a Marie Curie Innovative Training Network, which aims for the design, photo-optimization, and biological evaluation of photosensitizers for human health and food security applications.
Sophia Sarpaki
Sophia Sarpaki is a radiopharmaceutical chemist and obtained her Ph.D. diploma from the Chemistry Department of Bath University, on “Investigations into the Radiochemistry of Gallium- and Fluorine-Containing Compounds for Molecular Imaging Applications”. She holds the FELASSA certification for small animal handling. She works as a researcher and project manager on research preclinical imaging projects at BIOEMETCH. Her expertise lies in developing radiolabeling protocols for small molecules, biomolecules, and nanostructures, executing their necessary chemical analysis and performing their in vivo evaluation. Her scientific interest has a strong focus on cancer research, but she is also involved with projects related to cardiovascular diseases and stem cell therapy. She has participated in a variety of international research projects under the framework of EuroNanoMed, H2020, and ERC.
Panagiotis Papadimitroulas
Panagiotis Papadimitroulas is cofounder and Project Director of BIOEMTECH (www.bioemtech.com) since 2013. He holds a Ph.D. in Medical Physics (2015) awarded by the University of Patras. He has extensive expertise in the evaluation and optimization of clinical and preclinical dosimetry protocols, in Monte Carlo simulations, image processing tools, and advanced computational models. Since 2019, he gained a Post-Doc Research Grant from the State Scholarships Foundation (ΙΚΥ). He authored 2 chapter books related to internal dosimetry and computational tools, 18 publications in peer-review journals, and more than 60 announcements in international/national conferences. He has participated in more than 15 international and national research projects under the framework of FP7, COST, H2020, ERANET, NSRF. Since 2017, he is an official member of the OpenGATE collaboration.
Bruno Therrien
Bruno Therrien is an Associate professor at the University of Neuchatel, Switzerland. He studied chemistry at the University of Montreal and obtained his Ph.D. in 1998 from the University of Bern, Switzerland. After his Ph.D., he undertook several postdoctoral positions (Weizmann Institute, Massey University, Tokyo University), before returning to Switzerland. His main research interests are supramolecular chemistry and the biological applications of metalla-assemblies.
George Loudos
George Loudos is an Assistant Professor at the University of West Attica Athens and CEO and cofounder of BIOEMTECH. He has participated as a coordinator or partner in more than 15 EU projects, as well as two National Excellence grants and several smaller national and other projects. He has published over 120 articles in international journals and has >250 publications in conference proceedings and ∼1350 citations. He has given 60 invited lectures and holds one patent. He has been the organizer of many international conferences, workshops, and training schools. His research interests are focused on molecular imaging of nanoparticles and other biomolecules using nuclear medicine techniques, medical instrumentation, and he strongly supports interdisciplinary cooperation and education in the field of nanomedicine and molecular imaging.
| Abbreviations Used | |
| AFP | hepatocellular carcinoma markers |
| aPS | activatable photosensitizer |
| Arg | arginine |
| Asp | aspartate |
| AuNPs | gold nanoaprticles |
| BODIPY | boron-dipyrromethene |
| BOLD | blood oxygen-dependent level |
| BP | benzoporphyrin derivative |
| BPD-MA | benzoporphyrin derivative monoacid |
| C225 | EGFR antibody |
| CA125 | ovarian cancer marker |
| CA153 | breast tumor marker |
| CA199 | gastrointestinal tumor marker |
| CA242 | gastrointestinal tumor marker |
| CA724 | gastrointestinal tumor marker |
| CA-IX | (HIF)-1 regulated carbonic anhydrase-IX receptor |
| CAT | catalase |
| Ce6 | chlorin e6 |
| CEA | lung cancer tumor marker |
| CNC | cellulose nanocrystals |
| CT | computer tomography |
| Cu-ATSM | Diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) |
| Cyfra21–1 | lung cancer tumor marker |
| DBP-UiO | Hf–porphyrin nanoscale metal–organic framework |
| DLI | drug to light interval |
| DOTA | 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid |
| DOX | doxorubicin |
| DPP | diketopyrrolopyrrole |
| EGFR | epidermal growth factor receptor |
| EPR | enhanced permeability and a retention effect |
| FA | folic acid |
| FGR | fluorescence-guided resection |
| FMISO | fluoromisonidazole |
| FR | folate receptors |
| FRET | fluorescence resonance energy transfer |
| GLUT | glucose transporters |
| Gly | glycine |
| HCG | choriocarcinoma marker |
| HeLa | immortal cell line derived from cervical cancer cells |
| HIF | hypoxia-inducible factors |
| HpD | hematoporphyrin derivative |
| HSiNP | hollow SiNPs |
| ICG | indocyanine green |
| ISC | intersystem crossing |
| LDL | low density lipoprotein |
| MDR | multidrug resistance |
| MOF | metal–organic frameworks |
| MRI | magnetic resonance imaging |
| MSiNP | metal SiNPs |
| NI | nitrimidazole |
| NI-CP | (NI)-conjugated dithiophene-benzotriazole-containing polymer |
| NIR | near-infrared |
| NMI | nuclear medical imaging |
| NOTA | 1,4,7-triazacyclononane-1,4-diacetic acid |
| NP | nanoparticle |
| NSE | lung cancer tumor marker |
| OFI | optical fluorescence imaging |
| PAA | polyacrylamide |
| Pc | phthalocyanine |
| PDD | photodynamic diagnosis |
| PDT | photodynamic therapy |
| PEG | polyethylene glycol |
| PET | positron emission tomography |
| PIC | photimmunoconjugate |
| PLGA | poly(lactic-co-glycolic acid |
| PPIX | protoporphyrin IX |
| PS | photosensitizer |
| PSA | prostate cancer marker |
| Q | quencher particle |
| QD | quantum dots |
| QY | quantum yield |
| RGD | arginylglycylaspartic acid |
| ROS | reactive oxygen species |
| SiNP | silica nanoparticles |
| SK-BR-3 | human breast cancer cell line |
| SPECT | single-photon emission computed tomography |
| THPP | tris(3-hydroxypropyl)phosphine |
| TPC | 5-[4carboxyphenyl]-10,15,20-triphenyl-2,3-dihydroxychlorin |
| TR | transferrin receptor. |
References
ARTICLE SECTIONS
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- 9Soukos, N. S.; Hamblin, M. R.; Keel, S.; Fabian, R. L.; Deutsch, T. F.; Hasan, T. Epidermal Growth Factor Receptor-Targeted Immunophotodiagnosis and Photoimmunotherapy of Oral Precancer in Vivo. Cancer Res. 2001, 61, 4490– 4496[PubMed], [CAS], Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXktlWjs70%253D&md5=c13385de1e227db9fa7cb18bc002cacbEpidermal growth factor receptor-targeted immunophotodiagnosis and photoimmunotherapy of oral precancer in vivoSoukos, Nikolaos S.; Hamblin, Michael R.; Keel, Suzanne; Fabian, Richard L.; Deutsch, Thomas F.; Hasan, TayyabaCancer Research (2001), 61 (11), 4490-4496CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Immunophotodiagnosis uses a fluorescence-labeled monoclonal antibody (MAb) that recognizes a tumor-assocd. antigen to image the fluorescence emitted from the fluorophore-bound MAb that has localized in the tissue. It may be used to diagnose malignant or precancerous lesions, to delineate the margins for tumor resection, or as a feedback mechanism to assess response to treatment. In oral precancer, the epidermal growth factor receptor (EGFR) is overexpressed and could be used as a marker for early detection or as a target for therapy. The goal of this study was to test an anti-EGFR MAb (C225) coupled to either the near-IR fluorescent dye N,N'-di-carboxypentyl-indodicarbocyanine-5,5'-disulfonic acid for detection or a photochem. active dye (chlorine6) for therapy of early premalignancy in the hamster cheek pouch carcinogenesis model. Fluorescence levels in the carcinogen-treated tissue correlated with the histol. stage of the lesions when the C225-N,N'-di-carboxypentyl-indodicarbocyanine-5,5'-disulfonic acid conjugate was used but did not do so with the irrelevant conjugates. Discrete areas of clin. normal mucosa with high fluorescence (hot spots) were subsequently shown by histol. to contain dysplastic areas. The best contrast between normal and carcinogen-treated cheek pouches was found at 4-8 days after injection. To test the potential of immunophotodiagnosis as a feedback modality for therapeutic intervention, expts. were conducted with the same MAb conjugated to chlorine6 followed by illumination to reduce expression of the EGFR by a photodynamic effect. Subsequent immunophotodiagnosis showed that this treatment led to a significant redn. in fluorescence in the carcinogen-treated cheek pouch compared with nonilluminated areas. This difference between illuminated and dark areas was not seen in the normal cheek pouch. Taken together, the results demonstrate the potential for development of immunophotodiagnosis as a diagnostic tool and as a method of monitoring response to therapy and that the EGFR may be an appropriate target in head and neck cancer.
- 10Zheng, X.; Sallum, U. W.; Verma, S.; Athar, H.; Evans, C. L.; Hasan, T. Exploiting a Bacterial Drug-Resistance Mechanism: A Light-Activated Construct for the Destruction of MRSA. Angew. Chem., Int. Ed. 2009, 48, 2148– 2151, DOI: 10.1002/anie.200804804[Crossref], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXktFegtr4%253D&md5=aa3ee1067024a7174bae31b1b240fcdeExploiting a bacterial drug-resistance mechanism: a light-activated construct for the destruction of MRSAZheng, Xiang; Sallum, Ulysses W.; Verma, Sarika; Athar, Humra; Evans, Conor L.; Hasan, TayyabaAngewandte Chemie, International Edition (2009), 48 (12), 2148-2151CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)An enzyme-specific mol. construct exploits the overexpression of β-lactamase in several drug-resistant bacteria. Ed Specific photodynamic toxicity was detected towards β-lactam-resistant methicillin-resistant Staphylococcus aureus (MRSA), whereby the usual mechanism for antibiotic resistance (cleavage of the β-lactam ring) releases the phototoxic component from the prodrug.
- 11Zhong, W.; Celli, J. P.; Rizvi, I.; Mai, Z.; Spring, B. Q.; Yun, S. H.; Hasan, T. In Vivo High-Resolution Fluorescence Microendoscopy for Ovarian Cancer Detection and Treatment Monitoring. Br. J. Cancer 2009, 101, 2015– 2022, DOI: 10.1038/sj.bjc.6605436[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFaqtr7M&md5=4b2a5cf6e044243d4bc51f309d0565f0In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoringZhong, W.; Celli, J. P.; Rizvi, I.; Mai, Z.; Spring, B. Q.; Yun, S. H.; Hasan, T.British Journal of Cancer (2009), 101 (12), 2015-2022CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)Background: In patients with advanced ovarian cancer (OvCa), microscopic residual tumor nodules that remain after surgical debulking frequently escape detection by current treatment assessment methods and lead to disease recurrence. The aim of this study was to evaluate the use of high-resoln. fiber-optic fluorescence imaging of the clin. approved photodynamic therapy (PDT) agent benzoporphyin-deriv. monoacid ring A (BPD-MA) for detection of microscopic OvCa and for monitoring treatment response. Methods: Our fluorescence microendoscope consists of a flexible imaging fiber coupled to a custom epi-fluorescence system optimized for imaging BPD-MA, which, after a single administration, serves as both an imaging agent and a light-activated therapeutic agent. After characterization in an in vitro OvCa 3D model, we used the flexible imaging fiber to minimally invasively image the peritoneal cavity of a disseminated OvCa murine model using BPD-MA administered i.p. To evaluate longitudinal changes in response to treatment, we compared sets of images obtained before and after PDT with those from untreated mice imaged at the same time points. Results: By comparison with histopathol., we report an 86% sensitivity for tumor detection in vivo using the microendoscope. Using a custom routine to batch process-image data in the monitoring study, treated mice exhibited an av. decrease of 58.8% in tumor vols. compared with an increase of 59.3% in untreated controls (P<0.05). Conclusions: Our findings indicate the potential of this approach as a reporter of treatment outcome that could aid in the rational design of strategies to mitigate recurrent OvCa.
- 12Li, Y.; Wang, J.; Zhang, X.; Guo, W.; Li, F.; Yu, M.; Kong, X.; Wu, W.; Hong, Z. Highly Water-Soluble and Tumor-Targeted Photosensitizers for Photodynamic Therapy. Org. Biomol. Chem. 2015, 13, 7681– 7694, DOI: 10.1039/C5OB01035G[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpsF2ns7k%253D&md5=321d533f0a3356ccdde82d4735e8a1f2Highly water-soluble and tumor-targeted photosensitizers for photodynamic therapyLi, Yuxi; Wang, Jin; Zhang, Xiaoxiao; Guo, Wenjun; Li, Fu; Yu, Min; Kong, Xiuqi; Wu, Wenjie; Hong, ZhangyongOrganic & Biomolecular Chemistry (2015), 13 (28), 7681-7694CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)Biol. uses of photosensitizers in photodynamic therapy (PDT) often suffer from a lack of tumor selectivity; a strategy based on mol.-targeted cancer therapies could provide a promising soln. To synthesize new water-sol. phthalocyanines (Pcs) for bio-conjugation with peptides or antibodies, we developed a method to synthesize asym. substituted Pcs with both high water soly. and one monoamino group for conjugation with biol. agents for tumor homing, using folic acid as the ligand model to direct the modified Pcs into target cells. Here, we report studies on the syntheses and characterization of these Pcs. In vitro and in vivo assays prove that the high soly. characteristic can greatly increase the tumor targeting capability of Pcs by reducing non-specific uptake. This newly designed photosensitizer accumulated almost completely in tumor regions, with a negligible signal found in other tissues in the xenograft tumor model. These initial data provide strong evidence of the high specificity tumor targeting of Pcs with folate and tri-glycerol substitutions. Theor., the synthesized Pcs could be conveniently conjugated to many other ligands, endorsing the broad applicability of this method for tumor-targeted PDT.
- 13Celli, J. P.; Spring, B. Q.; Rizvi, I.; Evans, C. L.; Samkoe, K. S.; Verma, S.; Pogue, B. W.; Hasan, T. Imaging and Photodynamic Therapy: Mechanisms, Monitoring, and Optimization. Chem. Rev. 2010, 110, 2795– 2838, DOI: 10.1021/cr900300p[ACS Full Text], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXktVeqt7o%253D&md5=43f42186964bfb1227739a8acaf82077Imaging and Photodynamic Therapy: Mechanisms, Monitoring, and OptimizationCelli, Jonathan P.; Spring, Bryan Q.; Rizvi, Imran; Evans, Conor L.; Samkoe, Kimberley S.; Verma, Sarika; Pogue, Brian W.; Hasan, TayyabaChemical Reviews (Washington, DC, United States) (2010), 110 (5), 2795-2838CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review.
- 14Kharroubi Lakouas, D.; Huglo, D.; Mordon, S.; Vermandel, M. Nuclear Medicine for Photodynamic Therapy in Cancer: Planning, Monitoring and Nuclear PDT. Photodiagn. Photodyn. Ther. 2017, 18, 236– 243, DOI: 10.1016/j.pdpdt.2017.03.002[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmtlahsbk%253D&md5=de9343b97724f6c80c8fb527088ba36aNuclear medicine for photodynamic therapy in cancer: Planning, monitoring and nuclear PDTKharroubi Lakouas, Dris; Huglo, Damien; Mordon, Serge; Vermandel, MaximilienPhotodiagnosis and Photodynamic Therapy (2017), 18 (), 236-243CODEN: PPTHBF; ISSN:1572-1000. (Elsevier B.V.)A review. Photodynamic therapy (PDT) is a modality with promising results for the treatment of various cancers. PDT is increasingly included in the std. of care for different pathologies. This therapy relies on the effects of light delivered to photosensitized cells. At different stages of delivery, PDT requires imaging to plan, evaluate and monitor treatment. The contribution of mol. imaging in this context is important and continues to increase. In this article, we review the contribution of nuclear medicine imaging in oncol. to PDT for planning and therapeutic monitoring purposes. Several solns. have been proposed to plan PDT from nuclear medicine imaging. For instance, photosensitizer biodistribution has been evaluated with a radiolabeled photosensitizer or with conventional radiopharmaceuticals on positron emission tomog. The effects of PDT delivery have also been explored with specific SPECT or PET radiopharmaceuticals to evaluate the effects on cells (apoptosis, necrosis, proliferation, metab.) or vascular damage. Finally, the synergy between photosensitizers and radiopharmaceuticals has been studied considering the Cerenkov effect to activate photosensitized cells.
- 15Jokerst, J. V.; Lobovkina, T.; Zare, R. N.; Gambhir, S. S. Nanoparticle PEGylation for Imaging and Therapy. Nanomedicine 2011, 6, 715– 728, DOI: 10.2217/nnm.11.19[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsVajtro%253D&md5=960e4aed2f95aae187beeb7d6e5eb882Nanoparticle PEGylation for imaging and therapyJokerst, Jesse V.; Lobovkina, Tatsiana; Zare, Richard N.; Gambhir, Sanjiv S.Nanomedicine (London, United Kingdom) (2011), 6 (4), 715-728CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)A review. Nanoparticles are an essential component in the emerging field of nanomedical imaging and therapy. When deployed in vivo, these materials are typically protected from the immune system by polyethylene glycol (PEG). A wide variety of strategies to coat and characterize nanoparticles with PEG has established important trends on PEG size, shape, d., loading level, mol. wt., charge and purifn. Strategies to incorporate targeting ligands are also prevalent. This article presents a background to investigators new to stealth nanoparticles, and suggests some key considerations needed prior to designing a nanoparticle PEGylation protocol and characterizing the performance features of the product.
- 16Crawley, N.; Thompson, M.; Romaschin, A. Theranostics in the Growing Field of Personalized Medicine: An Analytical Chemistry Perspective. Anal. Chem. 2014, 86, 130– 160, DOI: 10.1021/ac4038812[ACS Full Text], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFSqsb3J&md5=96501281b0737b9f17c2500c784489a7Theranostics in the Growing Field of Personalized Medicine: An Analytical Chemistry PerspectiveCrawley, Niall; Thompson, Michael; Romaschin, AlexanderAnalytical Chemistry (Washington, DC, United States) (2014), 86 (1), 130-160CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)A review. The purpose of this article is more than a review of theranostics and nanoparticles. It is our intention to also pose questions and discuss the challenges of the future of this field. We attempt to show how, in our opinion; the anal. chemist can feature prominently in the upcoming successes of this field. This is a "hot" area of research and there is much that the anal. chemist can contribute moving forward. We will also introduce a new sub-field based on the first definition of theranostics above. Instrumental or macro-theranostics describes the development of macro-scale instruments capable of both diagnostics and therapy. In particular we introduce theranostic circuit devices (TCDs) that consist of extracorporeal circulation of the blood and the use of an inline imaging system with a therapeutic cartridge component to clean and remove harmful mols. or cells from the bloodstream.
- 17Kelkar, S. S.; Reineke, T. M. Theranostics: Combining Imaging and Therapy. Bioconjugate Chem. 2011, 22, 1879– 1903, DOI: 10.1021/bc200151q[ACS Full Text], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtV2jt77K&md5=54add18153e2ad4c9c2aa30ba97dbc6dTheranostics: Combining Imaging and TherapyKelkar, Sneha S.; Reineke, Theresa M.Bioconjugate Chemistry (2011), 22 (10), 1879-1903CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)A review. Employing theranostic nanoparticles, which combine both therapeutic and diagnostic capabilities in one dose, has promise to propel the biomedical field toward personalized medicine. This review presents an overview of different theranostic strategies developed for the diagnosis and treatment of disease, with an emphasis on cancer. Herein, therapeutic strategies such as nucleic acid delivery, chemotherapy, hyperthermia (photothermal ablation), photodynamic, and radiation therapy are combined with one or more imaging functionalities for both in vitro and in vivo studies. Different imaging probes, such as MRI contrast agents (T1 and T2 agents), fluorescent markers (org. dyes and inorg. quantum dots), and nuclear imaging agents (PET/SPECT agents), can be decorated onto therapeutic agents or therapeutic delivery vehicles in order to facilitate their imaging and, in so doing, gain information about the trafficking pathway, kinetics of delivery, and therapeutic efficacy; several such strategies are outlined. The creative approaches being developed for these classes of therapies and imaging modalities are discussed, and the recent developments in this field along with examples of technologies that hold promise for the future of cancer medicine are highlighted.
- 18Terreno, E.; Uggeri, F.; Aime, S. Image Guided Therapy: The Advent of Theranostic Agents. J. Controlled Release 2012, 161, 328– 337, DOI: 10.1016/j.jconrel.2012.05.028[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xot12jurs%253D&md5=47cafb00bcfdfee02ac05cc610f1f389Image guided therapy: The advent of theranostic agentsTerreno, Enzo; Uggeri, Fulvio; Aime, SilvioJournal of Controlled Release (2012), 161 (2), 328-337CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Theranostic agents represent a recently introduced class of imaging probes designed to offer to pharmacologists and physicians a robust tool for minimally invasive in vivo visualization of drug delivery/release and therapy monitoring. By means of these agents, novel strategies able to integrate diagnosis and therapy could be developed. This highly interdisciplinary research field is one of the more innovative products resulting from the synergism between mol. imaging and nanomedicine. Potential applications of theranosis include the in vivo assessment of drug biodistribution and accumulation at the target site, visualization of the drug release from a given nanocarrier, and real-time monitoring of the therapeutic outcome. The expected end-point of theranostic agents is to provide a fundamental support for the optimization of innovative diagnostic and therapeutic strategies that could contribute to emerging concepts in the field of the "personalized medicine". This perspective paper aims at providing the reader the basic principles of theranosis with a particular emphasis to the design of theranostic agents.
- 19Yoon, H. Y.; Jeon, S.; You, D. G.; Park, J. H.; Kwon, I. C.; Koo, H.; Kim, K. Inorganic Nanoparticles for Image-Guided Therapy. Bioconjugate Chem. 2017, 28, 124– 134, DOI: 10.1021/acs.bioconjchem.6b00512[ACS Full Text], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslGku7%252FM&md5=352e2f7f97fd9f4f56c7c5c6f58ad9efInorganic Nanoparticles for Image-Guided TherapyYoon, Hong Yeol; Jeon, Sangmin; You, Dong Gil; Park, Jae Hyung; Kwon, Ick Chan; Koo, Heebeom; Kim, KwangmeyungBioconjugate Chemistry (2017), 28 (1), 124-134CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)A review. Recently, nanotechnol. has provided significant advances in biomedical applications including diagnosis and therapy. In particular, nanoparticles have emerged as valuable outcomes of nanotechnol. due to their unique physicochem. properties based on size, shape, and surface properties. Among them, a large amt. of research has reported imaging and therapeutic applications using inorg. nanoparticles with special properties. Inorg. nanoparticles developed for imaging and therapy contain metal (Au), metal oxide (Fe3O4, WO3, WO2.9), semiconductor nanocrystal (quantum dots (QDs)), and lanthanide-doped upconversion nanoparticles (UCNPs). Based on their intrinsic properties, they can generate heat, reactive oxygen species (ROS), or energy transfer, so that they can be used for both imaging and therapy. In this review, the authors introduce biocompatible inorg. nanoparticles for image-guided thermal and photodynamic therapy, and discuss their promising results from in vitro and in vivo studies for biomedical applications.
- 20Jenni, S.; Sour, A. Molecular Theranostic Agents for Photodynamic Therapy (PDT) and Magnetic Resonance Imaging (MRI). Inorganics 2019, 7, 10, DOI: 10.3390/inorganics7010010[Crossref], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht1SjsL3O&md5=46778d963f5504fa0e6b4abc79b39feeMolecular theranostic agents for photodynamic therapy (PDT) and magnetic resonance imaging (MRI)Jenni, Sebastien; Sour, AngeliqueInorganics (2019), 7 (1), 10CODEN: INORCW; ISSN:2304-6740. (MDPI AG)Magnetic resonance imaging (MRI) is a powerful non-invasive diagnostic tool that can provide important insights for medical treatment monitoring and optimization. Photodynamic therapy (PDT), a minimally invasive treatment for various types of tumors, is drawing increasing interest thanks to its temporal and spatial selectivity. The combination of MRI and PDT offers real-time monitoring of treatment and can give significant information for drug-uptake and light-delivery parameters optimization. In this review we will give an overview of mol. theranostic agents that have been designed for their potential application in MRI and PDT.
- 21Dougherty, T. J. Hematoporphyrin Derivative for Detection and Treatment of Cancer. J. Surg. Oncol. 1980, 15, 209– 210, DOI: 10.1002/jso.2930150303[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL3M%252FltVOnug%253D%253D&md5=c6e613e85c5e06578f3268169e0c37dcHematoporphyrin derivative for detection and treatment of cancerDougherty T JJournal of surgical oncology (1980), 15 (3), 209-10 ISSN:0022-4790.There is no expanded citation for this reference.
- 22Allison, R. R. Photodynamic Therapy: Oncologic Horizons. Future Oncol. 2014, 10, 123– 142, DOI: 10.2217/fon.13.176[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvV2rsbbI&md5=b676b2bb7b36db28ec9e5ae99520e1dePhotodynamic therapy: oncologic horizonsAllison, Ron R.Future Oncology (2014), 10 (1), 123-124CODEN: FOUNBN; ISSN:1479-6694. (Future Medicine Ltd.)A review. Photodynamic therapy (PDT) is a light-based intervention with a long and successful clin. track record for both oncol. and non-malignancies. In cancer patients, a photosensitizing agent is i.v., orally or topically applied and allowed time to preferentially accumulate in the tumor region. Light of the appropriate wavelength and intensity to activate the particular photosensitizer employed is then introduced to the tumor bed. The light energy will activate the photosensitizer, which in the presence of oxygen should allow for creation of the toxic photodynamic reaction generating reactive oxygen species. The photodynamic reaction creates a cascading series of events including initiation of apoptotic and necrotic pathways both in tumor and neovasculature, leading to permanent lesion destruction often with upregulation of the immune system. Cutaneous phototoxicity from unintentional sunlight exposure remains the most common morbidity from PDT. This paper will highlight current research and outcomes from the basic science and clin. applications of oncol. PDT and interpret how these findings may lead to enhanced and refined future PDT.
- 23Calin, M. A.; Parasca, S. V. Photodynamic Therapy in Oncology. J. Optoelectron. Adv. Mater. 2006, 8, 1173– 1179
- 24Verma, S.; Watt, G. M.; Mai, Z.; Hasan, T. Strategies for Enhanced Photodynamic Therapy Effects. Photochem. Photobiol. 2007, 83, 996– 1005, DOI: 10.1111/j.1751-1097.2007.00166.x[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFGhurvE&md5=47011ef7222ca16fb6b7c829bfec16d4Strategies for enhanced photodynamic therapy effectsVerma, Sarika; Watt, Gregory M.; Mai, Zhiming; Hasan, TayyabaPhotochemistry and Photobiology (2007), 83 (5), 996-1005CODEN: PHCBAP; ISSN:0031-8655. (Blackwell Publishing, Inc.)A review. Photodynamic therapy (PDT) is a treatment modality for the selective destruction of cancerous and nonneoplastic pathologies that involves the simultaneous presence of light, oxygen and a light-activatable chem. called a photosensitizer (PS) to achieve a cytotoxic effect. The photophysics and mechanisms of cell killing by PDT have been extensively studied in recent years, and PDT has received regulatory approval for the treatment of a no. of diseases worldwide. As the application of this treatment modality expands with regard to both anatomical sites and disease stages, it will be important to develop strategies for enhancing PDT outcomes. This article focuses on two broad approaches for PDT enhancement:. (1) Mechanism-based combination treatments in which PDT and a second modality can be designed to either increase the susceptibility of tumor cells to PDT or nullify the treatment outcome-mitigating mol. responses triggered by PDT of tumors, and. (2) The more recent approaches of PS targeting, either by specific cellular function-sensitive linkages or via conjugation to macromols.
- 25Spring, B. Q.; Abu-Yousif, A. O.; Palanisami, A.; Rizvi, I.; Zheng, X.; Mai, Z.; Anbil, S.; Sears, R. B.; Mensah, L. B.; Goldschmidt, R.; Erdem, S. S.; Oliva, E.; Hasan, T. Selective Treatment and Monitoring of Disseminated Cancer Micrometastases in Vivo Using Dual-Function, Activatable Immunoconjugates. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, E933– E942, DOI: 10.1073/pnas.1319493111[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtlyltL0%253D&md5=f38a0ccfb5e65237477f2409c4d63bcdSelective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugatesSpring, Bryan Q.; Abu-Yousif, Adnan O.; Palanisami, Akilan; Rizvi, Imran; Zheng, Xiang; Mai, Zhiming; Anbil, Sriram; Sears, R. Bryan; Mensah, Lawrence B.; Goldschmidt, Ruth; Erdem, S. Sibel; Oliva, Esther; Hasan, TayyabaProceedings of the National Academy of Sciences of the United States of America (2014), 111 (10), E933-E942CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Drug-resistant micrometastases that escape std. therapies often go undetected until the emergence of lethal recurrent disease. Here, we show that it is possible to treat microscopic tumors selectively using an activatable immunoconjugate. The immunoconjugate is composed of self-quenching, near-IR chromophores loaded onto a cancer cell-targeting antibody. Chromophore phototoxicity and fluorescence are activated by lysosomal proteolysis, and light, after cancer cell internalization, enabling tumor-confined photocytotoxicity and resoln. of individual micrometastases. This unique approach not only introduces a therapeutic strategy to help destroy residual drug-resistant cells but also provides a sensitive imaging method to monitor micrometastatic disease in common sites of recurrence. Using fluorescence microendoscopy to monitor immunoconjugate activation and micrometastatic disease, we demonstrate these concepts of "tumor-targeted, activatable photoimmunotherapy" in a mouse model of peritoneal carcinomatosis. By introducing targeted activation to enhance tumor selectively in complex anatomical sites, this study offers prospects for catching early recurrent micrometastases and for treating occult disease.
- 26Chilakamarthi, U.; Giribabu, L. Photodynamic Therapy: Past, Present and Future. Chem. Rec. 2017, 17, 775– 802, DOI: 10.1002/tcr.201600121[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtV2ksA%253D%253D&md5=ca59db5a3ecd8874dbd7fcf56131f382Photodynamic Therapy: Past, Present and FutureChilakamarthi, Ushasri; Giribabu, LingamalluChemical Record (2017), 17 (8), 775-802CODEN: CRHEAK; ISSN:1528-0691. (Wiley-VCH Verlag GmbH & Co. KGaA)Though we crossed many milestones in the field of medicine and health care in eradicating some deadly diseases over the past decades, cancer remained a challenge taking the lives of millions of people and having adverse effects on the quality of life of survivors. Chemotherapy and radiotherapy, the two existing major treatment modalities, have severe side effects and patients undergoing these treatments experience unbearable pain. Consequently, clinicians and researchers are working for the alternate treatment regimens, which can provide complete cure with min. or no side effects. To this end, the present review highlights the major advances and future promises of photodynamic therapy, an emerging and promising therapeutic modality for combating cancer. We delve on various important aspects of photodynamic therapy including principle, mechanism of action, brief history and development of photosensitizers from first generation to the existing third generation, delivery strategies, development or suppression of immunity, combination therapy and future prospects.
- 27Juarranz, Á.; Jaén, P.; Sanz-Rodríguez, F.; Cuevas, J.; González, S. Photodynamic Therapy of Cancer. Basic Principles and Applications. Clin. Transl. Oncol. 2008, 10, 148– 154, DOI: 10.1007/s12094-008-0172-2[Crossref], [PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXls1Cisbk%253D&md5=def01f96d817e695b02b79f0f2f4b2a8Photodynamic therapy of cancer. Basic principles and applicationsJuarranz, Angeles; Jaen, Pedro; Sanz-Rodriguez, Francisco; Cuevas, Jesus; Gonzalez, SalvadorClinical & Translational Oncology (2008), 10 (3), 148-154CODEN: CTOLAM; ISSN:1699-048X. (Springer)A review. Photodynamic therapy (PDT) is a minimally invasive therapeutic modality approved for clin. treatment of several types of cancer and non-oncol. disorders. In PDT, a compd. with photosensitizing properties (photosensitizer, PS) is selectively accumulated in malignant tissues. The subsequent activation of the PS by visible light, preferentially in the red region of the visible spectrum (λ≥600 nm), where tissues are more permeable to light, generates reactive oxygen species, mainly singlet oxygen (1O2), responsible for cytotoxicity of neoplastic cells and tumor regression. There are three main mechanisms described by which 1O2 contributes to the destruction of tumors by PDT: direct cellular damage, vascular shutdown and activation of immune response against tumor cells. The advantages of PDT over other conventional cancer treatments are its low systemic toxicity and its ability to selectively destroy tumors accessible to light. Therefore, PDT is being used for the treatment of endoscopically accessible tumors such as lung, bladder, gastrointestinal and gynaecol. neoplasms, and also in dermatol. for the treatment of non-melanoma skin cancers (basal cell carcinoma) and precancerous diseases (actinic keratosis). Photofrin, ALA and its ester derivs. are the main compds. used in clin. trials, though newer and more efficient PSs are being evaluated nowadays.
- 28Huang, P.; Lin, J.; Wang, S.; Zhou, Z.; Li, Z.; Wang, Z.; Zhang, C.; Yue, X.; Niu, G.; Yang, M.; Cui, D.; Chen, X. Photosensitizer-Conjugated Silica-Coated Gold Nanoclusters for Fluorescence Imaging-Guided Photodynamic Therapy. Biomaterials 2013, 34, 4643– 4654, DOI: 10.1016/j.biomaterials.2013.02.063[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXksVOntbg%253D&md5=594d42d07d182e750e5d508177233434Photosensitizer-conjugated silica-coated gold nanoclusters for fluorescence imaging-guided photodynamic therapyHuang, Peng; Lin, Jing; Wang, Shouju; Zhou, Zhijun; Li, Zhiming; Wang, Zhe; Zhang, Chunlei; Yue, Xuyi; Niu, Gang; Yang, Min; Cui, Daxiang; Chen, XiaoyuanBiomaterials (2013), 34 (19), 4643-4654CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Multifunctional theranostics have recently been intensively explored to optimize the efficacy and safety of therapeutic regimens. In this work, a photo-theranostic agent based on chlorin e6 Ce6 photosensitizer-conjugated silica-coated gold nanoclusters [email protected] is strategically designed and prepd. for fluorescence imaging-guided photodynamic therapy PDT. The [email protected] shows the following features: (i) high Ce6 photosensitizer loading; (ii) no non-specific release of Ce6 during its circulation; (iii) significantly enhanced cellular uptake efficiency of Ce6, offering a remarkably improved photodynamic therapeutic efficacy compared to free Ce6; (iv) subcellular characterization of the nanoformula via both the fluorescence of Ce6 and plasmon luminescence of AuNCs; (v) fluorescence imaging-guided photodynamic therapy PDT. This photo-theranostics owns good stability, high water dispersibility and soly., non-cytotoxicity, and good biocompatibility, thus facilitating its biomedical applications, particularly for multi-modal optical, CT and photoacoustic PA imaging-guided PDT or sonodynamic therapy.
- 29Chen, R.; Zhang, L.; Gao, J.; Wu, W.; Hu, Y.; Jiang, X. Chemiluminescent Nanomicelles for Imaging Hydrogen Peroxide and Self-Therapy in Photodynamic Therapy. J. Biomed. Biotechnol. 2011, 2011, 1, DOI: 10.1155/2011/679492
- 30Iranifam, M. Analytical Applications of Chemiluminescence Methods for Cancer Detection and Therapy. TrAC, Trends Anal. Chem. 2014, 59, 156– 183, DOI: 10.1016/j.trac.2014.03.010[Crossref], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFyntbvP&md5=889502e288b2adcf7b0ad25f41a09569Analytical applications of chemiluminescence methods for cancer detection and therapyIranifam, MortazaTrAC, Trends in Analytical Chemistry (2014), 59 (), 156-183CODEN: TTAEDJ; ISSN:0165-9936. (Elsevier B. V.)A review. Cancer is one of the most life-threatening diseases and a leading cause of death and disability for humans. The current state of the art in chemiluminescence (CL) detection methods provides clinicians and researchers interested in oncol. with efficient tools for early detection and accurate diagnosis of cancer. In this context, CL methods are powerful with the capability of detecting cancerous cells and cancer biomarkers, among other applications. Moreover, these methods can aid in increasing the survival chances of cancer patients undergoing chemotherapy and radiotherapy by sensitive monitoring of their progress when undergoing treatment. This article reviews the literature on the applications of CL methods in cancer detection and therapy (e.g., detn. of circulating tumor cells, cancer biomarkers and anticancer drugs, and photodynamic therapy as a light-delivery system and dosimetry tool).
- 31Laptev, R.; Nisnevitch, M.; Siboni, G.; Malik, Z.; Firer, M. A. Intracellular Chemiluminescence Activates Targeted Photodynamic Destruction of Leukaemic Cells. Br. J. Cancer 2006, 95, 189– 196, DOI: 10.1038/sj.bjc.6603241[Crossref], [PubMed], [CAS], Google Scholar31Intracellular chemiluminescence activates targeted photodynamic destruction of leukemic cellsLaptev, R.; Nisnevitch, M.; Siboni, G.; Malik, Z.; Firer, M. A.British Journal of Cancer (2006), 95 (2), 189-196CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)Photodynamic therapy (PDT) involves a two-stage process. A light-absorbing photosensitizer (Ps) is endocytosed and then stimulated by light, inducing transfer of energy to a cytoplasmic acceptor mol. and the generation of reactive oxygen species that initiate damage to cellular membrane components and cytolysis. The expanded use of PDT in the clinic is hindered by the lack of Ps target-cell specificity and the limited tissue penetration by external light radiation. This study demonstrates that bioconjugates composed of transferrin and hematoporphyrin (Tf-Hp), significantly improve the specificity and efficiency of PDT for erythroleukemic cells by a factor of almost seven-fold. Fluorescence microscopy showed that the conjugates accumulate in intracellular vesicles whereas free Hp was mostly membrane bound. Expts. with cells deliberately exposed to Tf-Hp athttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmvFajsbw%253D&md5=21ef59748c36aaedeb938d4f8809b14532Theodossiou, T.; Hothersall, J. S.; Woods, E. A.; Okkenhaug, K.; Jacobson, J.; MacRobert, A. J. Firefly Luciferin-Activated Rose Bengal: In Vitro Photodynamic Therapy by Intracellular Chemiluminescence in Transgenic NIH 3T3 Cells. Cancer Res. 2003, 63, 1818– 1821[PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXivFyns7o%253D&md5=7818a70c9b8d6add3563bac3de176933Firefly Luciferin-activated Rose Bengal: In Vitro Photodynamic Therapy by Intracellular Chemiluminescence in Transgenic NIH 3T3 CellsTheodossiou, Theodossis; Hothersall, John S.; Woods, Elizabeth A.; Okkenhaug, Klaus; Jacobson, Jake; MacRobert, Alexander J.Cancer Research (2003), 63 (8), 1818-1821CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Photodynamic therapy (PDT) of cancer (1 , 2) is a well-established treatment modality that uses light excitation of a photosensitive substance to produce oxygen-related cytotoxic intermediates, such as singlet oxygen or free radicals (3 , 4). Although PDT is advantageous over other forms of cancer treatments because of its limited side effects, its main disadvantage is the poor accessibility of light to more deeply lying malignancies. External light sources such as lasers or lamps can be applied either noninvasively to reach tumors that lie well within the penetration depth of the light or in a minimally invasive fashion (interstitial treatments) in which optical fibers are placed intratumorally through needles. Even with the second approach, light distribution over the tumor is not homogeneous and nonidentified metastatic disease is left untreated. CL, the chem. prodn. of light, is exemplified by firefly light emission mediated by the enzymic (luciferase + ATP) oxidn. of D-luciferin to oxyluciferin (5) . This mobile light source is a targetable alternative to external sources of illumination. Here we show the in vitro photodynamic effect of rose bengal activated by intracellular generation of light, in luciferase-transfected NIH 3T3 murine fibroblasts.33Calixto, G.; Bernegossi, J.; de Freitas, L.; Fontana, C.; Chorilli, M. Nanotechnology-Based Drug Delivery Systems for Photodynamic Therapy of Cancer: A Review. Molecules 2016, 21, 342, DOI: 10.3390/molecules21030342[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28fgs1Chtw%253D%253D&md5=b465d464abfaee5f95d6822157eb9e68Nanotechnology-Based Drug Delivery Systems for Photodynamic Therapy of Cancer: A ReviewCalixto Giovana Maria Fioramonti; Bernegossi Jessica; Chorilli Marlus; de Freitas Laura Marise; Fontana Carla RaquelMolecules (Basel, Switzerland) (2016), 21 (3), 342 ISSN:.Photodynamic therapy (PDT) is a promising alternative approach for improved cancer treatment. In PDT, a photosensitizer (PS) is administered that can be activated by light of a specific wavelength, which causes selective damage to the tumor and its surrounding vasculature. The success of PDT is limited by the difficulty in administering photosensitizers (PSs) with low water solubility, which compromises the clinical use of several molecules. Incorporation of PSs in nanostructured drug delivery systems, such as polymeric nanoparticles (PNPs), solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), gold nanoparticles (AuNPs), hydrogels, liposomes, liquid crystals, dendrimers, and cyclodextrin is a potential strategy to overcome this difficulty. Additionally, nanotechnology-based drug delivery systems may improve the transcytosis of a PS across epithelial and endothelial barriers and afford the simultaneous co-delivery of two or more drugs. Based on this, the application of nanotechnology in medicine may offer numerous exciting possibilities in cancer treatment and improve the efficacy of available therapeutics. Therefore, the aim of this paper is to review nanotechnology-based drug delivery systems for photodynamic therapy of cancer.34Agostinis, P.; Berg, K.; Cengel, K. A.; Foster, T. H.; Girotti, A. W.; Gollnick, S. O.; Hahn, S. M.; Hamblin, M. R.; Juzeniene, A.; Kessel, D.; Korbelik, M.; Moan, J.; Mroz, P.; Nowis, D.; Piette, J.; Wilson, B. C.; Golab, J. Photodynamic Therapy of Cancer: An Update. Ca-Cancer J. Clin. 2011, 61, 250– 281, DOI: 10.3322/caac.20114[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MnkslajtQ%253D%253D&md5=81f4bb716e0dd1967c4819f5593cf109Photodynamic therapy of cancer: an updateAgostinis Patrizia; Berg Kristian; Cengel Keith A; Foster Thomas H; Girotti Albert W; Gollnick Sandra O; Hahn Stephen M; Hamblin Michael R; Juzeniene Asta; Kessel David; Korbelik Mladen; Moan Johan; Mroz Pawel; Nowis Dominika; Piette Jacques; Wilson Brian C; Golab JakubCA: a cancer journal for clinicians (2011), 61 (4), 250-81 ISSN:.Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment.35Zheng, Y.; Yin, G.; Le, V.; Zhang, A.; Lu, Y.; Yang, M.; Fei, Z.; Liu, J. Hypericin-Based Photodynamic Therapy Induces a Tumor-Specific Immune Response and an Effective DC-Based Cancer Immunotherapy. Biochem. Pharmacol. 2014, 1, DOI: 10.1016/j.bcp.2014.01.03636Theodossiou, T. A.; Hothersall, J. S.; De Witte, P. A.; Pantos, A.; Agostinis, P. The Multifaceted Photocytotoxic Profile of Hypericin. Mol. Pharmaceutics 2009, 6, 1775– 1789, DOI: 10.1021/mp900166q[ACS Full Text], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFOiurvM&md5=6707d16cda4a15f52b0681d1e4bfcaa4The Multifaceted Photocytotoxic Profile of HypericinTheodossiou, Theodossis A.; Hothersall, John S.; De Witte, Peter A.; Pantos, Alexandros; Agostinis, PatriziaMolecular Pharmaceutics (2009), 6 (6), 1775-1789CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)A review. Photodynamic therapy (PDT) is an established anticancer treatment employing a phototoxin (photosensitizer), visible light and oxygen. The latter is photochem. converted into reactive oxygen species, which are highly toxic to the cells. Hypericin, a natural pigment of hypericum plants, is prominent among photosensitizers. The unique perylenequinone structure of hypericin is responsible for its intriguing multifaceted photochem. cytotoxicity. The diverse photodynamic action of hypericin targets a range of subcellular organelles most importantly the mitochondria and the endoplasmic reticulum (ER)-Golgi complex. Hypericin exerts its phototoxicity through intricate mechanisms, implicating key proteins, vital enzymes, organelle membranes and changes in cellular homeostasis. This, depending on drug and light administration conditions, leads to cell death, which occurs mainly by the induction of apoptosis and/or necrosis. Cell photosensitization with hypericin is also assocd. with the stimulation of macroautophagy, which may promote cell demise when the apoptotic machinery is defective. Herein, we aim to integrate the most important findings with regard to hypericin photocytotoxicity, into a unified scenario, detailing its potential in cancer photomedicine.37Liu, X.; Jiang, C.; Li, Y.; Liu, W.; Yao, N.; Gao, M.; Ji, Y.; Huang, D.; Yin, Z.; Sun, Z.; Ni, Y.; Zhang, J. Evaluation of Hypericin: Effect of Aggregation on Targeting Biodistribution. J. Pharm. Sci. 2015, 104, 215– 222, DOI: 10.1002/jps.24230[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFWitLzM&md5=dd8b285aaba9bb8c4a8f0a0de81d36b3Evaluation of hypericin. Effect of aggregation on targeting biodistributionLiu, Xuejiao; Jiang, Cuihua; Li, Yue; Liu, Wei; Yao, Nan; Gao, Meng; Ji, Yun; Huang, Dejian; Yin, Zhiqi; Sun, Ziping; Ni, Yicheng; Zhang, JianJournal of Pharmaceutical Sciences (2015), 104 (1), 215-222CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)Hypericin (Hy) has shown great promise as a necrosis-avid agent in cancer imaging and therapy. Given the highly hydrophobic and π-conjugated planarity characteristics, Hy tends to form aggregates. To investigate the effect of aggregation on targeting biodistribution, nonaggregated formulation (Non-Ag), aggregated formulation with overconcd. Hy in DMSO (Ag-DMSO) soln., and aggregated formulation in water soln. (Ag-water) were selected by fluorescence measurement. They were labeled with 131I and evaluated for the necrosis affinity in rat model of reperfused hepatic infarction by gamma counting and autoradiog. The radioactivity ratio of necrotic liver/normal liver was 17.1, 7.9, and 6.4 for Non-Ag, Ag-DMSO, and Ag-water, resp. The accumulation of two aggregated formulations (Ag-DMSO and Ag-water) in organs of mononuclear phagocyte system (MPS) was 2.62 ± 0.22 and 3.96 ± 0.30 %ID/g in the lung, and 1.44 ± 0.29 and 1.51 ± 0.23 %ID/g in the spleen, resp. The biodistribution detected by autoradiog. showed the same trend as by gamma counting. In conclusion, the Non-Ag showed better targeting biodistribution and less accumulation in MPS organs than aggregated formulations of Hy. The two aggregated formulations showed significantly lower and higher accumulation in targeting organ and MPS organs, resp. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.38Ghosh, S.; Banerjee, S.; Sil, P. C. The Beneficial Role of Curcumin on Inflammation, Diabetes and Neurodegenerative Disease: A Recent Update. Food Chem. Toxicol. 2015, 83, 111– 124, DOI: 10.1016/j.fct.2015.05.022[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVWgu7fJ&md5=f8e58560062b009bf029808ca161750aThe beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent updateGhosh, Shatadal; Banerjee, Sharmistha; Sil, Parames C.Food and Chemical Toxicology (2015), 83 (), 111-124CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)The concept of using phytochems. has ushered in a new revolution in pharmaceuticals. Naturally occurring polyphenols (like curcumin, morin, resveratrol, etc.) have gained importance because of their minimal side effects, low cost and abundance. Curcumin (diferuloylmethane) is a component of turmeric isolated from the rhizome of Curcuma longa. Research for more than two decades has revealed the pleiotropic nature of the biol. effects of this mol. More than 7000 published articles have shed light on the various aspects of curcumin including its antioxidant, hypoglycemic, anti-inflammatory and anti-cancer activities. Apart from these well-known activities, this natural polyphenolic compd. also exerts its beneficial effects by modulating different signalling mols. including transcription factors, chemokines, cytokines, tumor suppressor genes, adhesion mols., microRNAs, etc. Oxidative stress and inflammation play a pivotal role in various diseases like diabetes, cancer, arthritis, Alzheimer's disease and cardiovascular diseases. Curcumin, therefore, could be a therapeutic option for the treatment of these diseases, provided limitations in its oral bioavailability can be overcome. The current review provides an updated overview of the metab. and mechanism of action of curcumin in various organ pathophysiologies. The review also discusses the potential for multifunctional therapeutic application of curcumin and its recent progress in clin. biol.39Wikene, K. O.; Hegge, A. B.; Bruzell, E.; Tonnesen, H. H. Formulation and Characterization of Lyophilized Curcumin Solid Dispersions for Antimicrobial Photodynamic Therapy (Apdt): Studies on Curcumin and Curcuminoids LII. Drug Dev. Ind. Pharm. 2015, 41, 969– 977, DOI: 10.3109/03639045.2014.919315[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpt1KltLg%253D&md5=a9bf0fae7d791b8c285e2f66dcac215bFormulation and characterization of lyophilized curcumin solid dispersions for antimicrobial photodynamic therapy (aPDT): studies on curcumin and curcuminoids LIIWikene, Kristine Opsvik; Hegge, Anne Bee; Bruzell, Ellen; Tonnesen, Hanne HjorthDrug Development and Industrial Pharmacy (2015), 41 (6), 969-977CODEN: DDIPD8; ISSN:0363-9045. (Informa Healthcare)Context: Bacterial resistance to antibiotics is increasing and alternative antibacterial treatments like antimicrobial photodynamic therapy (aPDT) are needed. Curcumin is under investigation as a potential photosensitizer in aPDT. Objective: The purpose of this study was to develop rapidly dissolving formulations of curcumin that could photoinactivate both Gram-pos. and Gram-neg. bacteria. Materials and methods: Curcumin solid dispersions with methyl-β-cyclodextrin and hyaluronic acid (HA), hydroxypropyl methylcellulose (HPMC) or both HA and HPMC were prepd. through lyophilization. The lyophilizates were characterized by curcumin drug load [% (wt./wt.)], differential scanning calorimetry, photostability, thermal stability, their ability to form supersatd. solns. and by in vitro photoinactivation of Enterococcus faecalis and Escherichia coli. Results and discussion: The lyophilizates were amorphous solid dispersions with a curcumin drug load in the range of 1.4-5.5% (wt./wt.) depending on the included polymer and the ratio between curcumin and the cyclodextrin. The lyophilizates were photolabile, but thermally stable and dissolved rapidly in contact with water to form supersatd. solns. Selected lyophilizates demonstrated >log 6 redn. of colony forming units/mL of both E. faecalis and E. coli after exposure to low curcumin concns. (0.5-10 μM) and blue light dose (11-16 J/cm2). The high drug load of the lyophilizates, rapid dissoln., ability to form relatively stable supersatd. solns. and the very high phototoxicity towards both E. faecalis and E. coli make these lyophilizates suitable for in vivo aPDT. Conclusions: This treatment with optimized curcumin formulations should be explored as an alternative to topical antibiotics in the treatment of wound infections.40Bernd, A. Visible Light And/Or UVA Offer a Strong Amplification of the Anti-Tumor Effect of Curcumin. Phytochem. Rev. 2014, 13, 183– 189, DOI: 10.1007/s11101-013-9296-2[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXislClt7o%253D&md5=9db0eac5349f398dd3de118fd6abd42aVisible light and/or UVA offer a strong amplification of the anti-tumor effect of curcuminBernd, AugustPhytochemistry Reviews (2014), 13 (1), 183-189CODEN: PRHEBS; ISSN:1568-7767. (Springer)A review. Curcumin, a dietary pigment from the plant Curcuma longa, inhibits cell proliferation and induces apoptosis in different cell lines. The therapeutic benefit is hampered by a very low absorption after trans-dermal or oral application. Therefore, great efforts were undertaken to enhance the effectiveness of curcumin. Recently, it was demonstrated that curcumin offers the described effects also at low concns. (0.2-1 μg/mL) when applied in combination with UVA or visible light. The efficacy of this combination was shown in human epidermal keratinocytes and in a panel of other cell species in vitro as well as in a xenograft tumor model with A431 tumor cells injected s.c. in the flanks of NMRI nude mice in vivo. The treatment of keratinocytes with curcumin and light resulted in the inhibition of cell growth, and in the induction of apoptosis, whereas no toxic cell membrane damage was detectable. The treatment of tumor bearing nude mice with curcumin and visible light resulted in reduced tumor vols., reduced proliferation rates, and the induction of apoptosis in the tumors. On the mol. level inhibition of extracellular regulated kinases 1/2 and epidermal growth factor receptor was obsd. which may aid to inhibition of proliferation and induction of apoptosis. This review covers the experiences of the new combination treatment of human tumors.41Leite, D. P. V.; Paolillo, F. R.; Parmesano, T. N.; Fontana, C. R.; Bagnato, V. S. Effects of Photodynamic Therapy With Blue Light and Curcumin as Mouth Rinse for Oral Disinfection: A Randomized Controlled Trial. Photomed. Laser Surg. 2014, 32, 627– 632, DOI: 10.1089/pho.2014.3805[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVKrsL%252FI&md5=70966da7d6d54531b474cda96eeab749Effects of Photodynamic Therapy with Blue Light and Curcumin as Mouth Rinse for Oral Disinfection: A Randomized Controlled TrialLeite, Diego Portes Vieira; Paolillo, Fernanda Rossi; Parmesano, Thiago Nogueira; Fontana, Carla Raquel; Bagnato, Vanderlei SalvadorPhotomedicine and Laser Surgery (2014), 32 (11), 627-632CODEN: PLDHA8; ISSN:1549-5418. (Mary Ann Liebert, Inc.)Objective: The purpose of this study was to evaluate the effects of the antimicrobial photodynamic therapy (a-PDT) with blue light and curcumin on oral disinfection during the 2 h after treatment. Background data: a-PDT is a technique that can potentially affect the viability of bacterial cells, with selective action targeting only areas with photosensitizer accumulation. Materials and methods: A randomized controlled trial was undertaken. Twenty-seven adults were randomly divided into three groups: (1) the PDT group, which was treated with the drug, curcumin, and blue light (n=9); (2) the light group, which was treated only with the blue light, and no drug (n=9) and; (3) the curcumin group, which was treated only with the drug, curcumin, and no light (n=9). The irradn. parameters were: blue light-emitting diode (LED) illumination (455±30 nm), 400 mW of av. optical power, 5 min of application, illumination area of 0.6 cm2, 600 mW/cm2 of intensity, and 200 J/cm2 of fluence. A curcumin concn. of 30 mg/L was used. The saliva samples were collected for bacterial counts at baseline and after the exptl. phases (immediately after treatment, and 1 and 2 h after treatment). Serial dilns. were performed, and the resulting samples were cultured on blood agar plates in microaerophilic conditions. The no. of colony-forming units (CFU) was detd. Results: The PDT group showed a significant redn. of CFU immediately after treatment (post-treatment) with PDT (5.71±0.48, p=0.001), and 1 h (5.14±0.92, p=0.001) and 2 h (5.35±0.76, p=0.001) after treatment, compared with pretreatment (6.61±0.82). There were no significant changes for the light group. The curcumin group showed a significant increase of CFU 1 h after treatment (6.77±0.40, p=0.02) compared with pretreatment (5.57±0.91) falling to baseline values at 2 h after treatment (5.58±0.70). Conclusions: The PDT group showed significant difference in microbial redn. (p<0.05) compared with both the light and curcumin groups until 2 h post-treatment. The new blue LED device for PDT using curcumin may be used for redn. of salivary microorganisms, leading to overall disinfection of the mouth (e.g., mucosa, tongue, and saliva), but new protocols should be explored.42Li, T.; Hou, X.; Deng, H.; Zhao, J.; Huang, N.; Zeng, J.; Chen, H.; Gu, Y. Liposomal Hypocrellin B as a Potential Photosensitizer for Age-Related Macular Degeneration: Pharmacokinetics, Photodynamic Efficacy, and Skin Phototoxicity in Vivo. Photochem. Photobiol. Sci. 2015, 14, 972– 981, DOI: 10.1039/C4PP00412D[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXktVCru70%253D&md5=8b2e424c8fe901ce286a08c7142d18f9Liposomal hypocrellin B as a potential photosensitizer for age-related macular degeneration: pharmacokinetics, photodynamic efficacy, and skin phototoxicity in vivoLi, Tinghui; Hou, Xiaobin; Deng, Hong; Zhao, Jingquan; Huang, Naiyan; Zeng, Jing; Chen, Hongxia; Gu, YingPhotochemical & Photobiological Sciences (2015), 14 (5), 972-981CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)Photodynamic therapy (PDT) has been successfully implemented as a treatment for wet age-related macular degeneration (AMD), but very few photosensitizers have been developed for clin. use. Herein, we describe a novel formulation of liposomal hypocrellin B (LHB) that was prepd. by high-pressure homogenization. The encapsulation efficiency and PDT efficacy in vitro of this new prepn. were found to remain nearly const. over 1 yr. Moreover, LHB is rapidly cleared from the blood, with a half-life of 2.319 ± 0.462 h and a very low serum concn. at 24 h after injection. Testing in a rat model of choroidal neovascularization (CNV) showed that leakage of blood vessels in CNV lesions was significantly reduced when LHB PDT was given at a dose of 1 mg kg-1 along with yellow laser irradn.; the damage to the collateral retina and the retinal pigment epithelium was minimal. Skin phototoxicity assays showed that only two of the 200 mice given a 4 mg per kg dose of LHB experienced an inflammatory reaction in the auricle irradiated at 24 h after dosing. These data collectively indicate that LHB may be a safe and effective photosensitizer for vascular-targeted PDT of AMD.43Zhenjun, D.; Lown, J. W. Hypocrellins and Their Use in Photosensitization. Photochem. Photobiol. 1990, 52, 609– 616, DOI: 10.1111/j.1751-1097.1990.tb01807.x[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3M7jsVamsA%253D%253D&md5=7e9e59d181a240b48b37f8227217c899Hypocrellins and their use in photosensitizationZhenjun D; Lown J WPhotochemistry and photobiology (1990), 52 (3), 609-16 ISSN:0031-8655.Hypocrellins A and B are pigments which are isolated from parasitic fungi Hypocrella bambuase (B. et Br) sacc. and Shiraia bambusicola P. Heen found in the People's Republic of China (P.R.C.) and Sri Lanka respectively. These agents, which belong to the general class of perylene quinonoid pigments, have a long history of traditional medicinal agents especially in the P.R.C. Recently their marked photosensitizing properties have been established and exploratory studies initiated. This effort has led to the realization of the potential of the hypocrellins for the photodynamic therapy of tumors. The review summarizes the chemical and photophysical properties of the hypocrellins and their derivatives as well as studies on photosensitization to date at the molecular, cellular and in vivo levels, and their prospects as PDT agents.44Makdoumi, K.; Bäckman, A.; Mortensen, J.; Crafoord, S. Evaluation of Antibacterial Efficacy of Photo-Activated Riboflavin Using Ultraviolet Light (UVA). Graefe's Arch. Clin. Exp. Ophthalmol. 2010, 248, 207– 212, DOI: 10.1007/s00417-009-1231-2[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtVagsQ%253D%253D&md5=3e7abe61dbe79d17c856cc8ae80cfc66Evaluation of antibacterial efficacy of photo-activated riboflavin using ultraviolet light (UVA)Makdoumi, Karim; Baeckman, Anders; Mortensen, Jes; Crafoord, SvenGraefe's Archive for Clinical and Experimental Ophthalmology (2010), 248 (2), 207-212CODEN: GACODL; ISSN:0721-832X. (Springer)Background: To evaluate the antibacterial efficacy of photo-activated riboflavin using UV A (UVA) on three bacterial strains commonly detected in keratitis. Methods: Three bacterial strains (Staphylococcus epidermidis, Staphylococcus aureus and Pseudomonas aeruginosa) were cultured on blood/hematin-agar plates and dispersed in PBS. Dispersion was done of 10 μl of bacterial stock-solns. in 90 μl of RPMI, where different riboflavin molarities had been added, to achieve a bacterial concn. of 1-4 × 10 4/mL. Riboflavin end molarities before illumination were 0, 100, 200, 300 and 400 μM. Each soln. had a neg. control. The solns. were illuminated with UVA (365 nm) for 30 min (5.4 J/cm2) and then continued for a total time of 60 min (10.8 J/cm2). A count of CFU was conducted after incubation and results compared. Results: In all tested strains, a slight decrease of bacteria was seen when exposed to UV for 30 min. A doubling of the UV dose showed a marked decrease of bacterial count in all bacteria tested. The combination of UV and riboflavin showed a more extensive redn. of CFU, confirming an interaction effect between UV and riboflavin. Conclusion: Riboflavin photo-activation using UVA (365 nm) can achieve an extensive eradication of bacteria, and the combination is more potent in reducing bacterial no. than UV alone.45Ettinger, A.; Miklauz, M. M.; Bihm, D. J.; Maldonado-Codina, G.; Goodrich, R. P. Preparation of Cryoprecipitate from Riboflavin and UV Light-Treated Plasma. Transfus. Apher. Sci. 2012, 46, 153– 158, DOI: 10.1016/j.transci.2012.01.004[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38zhslalsg%253D%253D&md5=03b3cf522e68a6ccd4b4f8d70224b585Preparation of cryoprecipitate from riboflavin and UV light-treated plasmaEttinger Anna; Miklauz Meghan M; Bihm David J; Maldonado-Codina Gabriela; Goodrich Raymond PTransfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis (2012), 46 (2), 153-8 ISSN:1473-0502.BACKGROUND AND OBJECTIVES: The Mirasol® pathogen reduction technology system for plasma is based on a riboflavin and UV light treatment process resulting in pathogen inactivation due to irreversible, photochemically induced damage of nucleic acids. This study was undertaken to evaluate the possibility of making pathogen reduced cryoprecipitate from riboflavin and UV light- treated plasma that meets the quality requirements specified by UK and European guidelines for untreated cryoprecipitate. MATERIALS AND METHODS: Cryoprecipitate was made from riboflavin and UV light-treated plasma. Plasma units were thawed over a 20 h period at 4°C, and variable centrifugation settings (from 654 g for 2 min to 5316 g for 6 min) were applied to identify the optimal centrifugation condition. Plasma proteins in cryoprecipitate units were characterized on a STA Compact, Diagnostica STAGO and Siemens BCS analyzer. RESULTS: Neither the centrifugation speed or time appeared to have an effect on the quality of the final cryoprecipitate product; however the initial solubilization of the cryoprecipitate product was found to be easier at the lower centrifugation setting (654 g for 2 min). Cryoprecipitate units prepared from Mirasol-treated plasma demonstrated protein levels that were less than levels in untreated products, but were on average 93 IU/unit, 262 mg/unit and 250 IU/unit for FVIII, fibrinogen and von Willebrand ristocetin cofactor activity, respectively. CONCLUSION: Cryoprecipitate products prepared from Mirasol-treated plasma using a centrifugation method contain levels of fibrinogen, FVIII and von Willebrand ristocetin cofactor activity, that meet both the European and UK guidelines for untreated cryoprecipitate. Flexibility in centrifugation conditions should allow blood banks to use their established centrifugation settings to make cryoprecipitate from Mirasol-treated plasma.46Papaioannou, L.; Miligkos, M.; Papathanassiou, M. Corneal Collagen Cross-Linking for Infectious Keratitis: A Systematic Review and Meta-Analysis. Cornea 2016, 35, 62– 71, DOI: 10.1097/ICO.0000000000000644[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28zmtFersA%253D%253D&md5=ed7151382dd7de05a81eb72f3d1d4195Corneal Collagen Cross-Linking for Infectious Keratitis: A Systematic Review and Meta-AnalysisPapaioannou Lamprini; Miligkos Michael; Papathanassiou MiltiadisCornea (2016), 35 (1), 62-71 ISSN:.PURPOSE: To assess the efficacy of corneal collagen cross-linking (CXL) in the management of infectious keratitis. METHODS: Comprehensive literature search was performed in MEDLINE/PubMed and Cochrane Central Register of Controlled Trials using combinations of the following search terms: "corneal collagen cross linking" or "photoactivated riboflavin" or "UVA light and riboflavin" and "infectious keratitis" or "corneal ulcer." Last search was on March 19, 2015. Extracted data from individual studies were summarized and summary proportions of eyes healed and complications for different subgroups were estimated. RESULTS: Twenty-five studies were included (2 randomized controlled trials, 13 case series, and 10 case reports) with a total of 210 eyes of 209 patients, of which 175 eyes underwent CXL. Causative microorganisms were bacteria, fungi, acanthamoeba, and Herpes simplex virus in 96, 32, 11, and 2 cases, respectively. Coinfections were present in 13 and cause was inconclusive in 21 cases. Sixteen of 175 eyes received no additional antibiotics, whereas 159 underwent CXL as an adjunct to antimicrobial treatment. Proportion of eyes healed with CXL was 87.2% (95% confidence interval (CI), 81.9%, 91.8%). For bacterial keratitis, the proportion of eyes healed was 85.7% (95% CI, 78.5%, 91.7%), whereas 10/11 and 25/32 eyes with acanthamoeba and fungal keratitis, respectively, were healed (available data not sufficient to provide a valid proportion analysis). Treatment resulted in corneal melting and tectonic keratoplasty in both Herpes simplex virus cases. CONCLUSIONS: CXL seems promising in the management of infectious keratitis, excluding viral infections. However, more randomized controlled trials are required to assess its efficacy.47Maisch, T.; Eichner, A.; Späth, A.; Gollmer, A.; König, B.; Regensburger, J.; Bäumler, W. Fast and Effective Photodynamic Inactivation of Multiresistant Bacteria by Cationic Riboflavin Derivatives. PLoS One 2014, 9, e111792, DOI: 10.1371/journal.pone.0111792[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtleks78%253D&md5=03002bb88b715070b6ed2f7b214e9f73Fast and effective photodynamic inactivation of multiresistant bacteria by cationic riboflavin derivativesMaisch, Tim; Eichner, Anja; Spaeth, Andreas; Gollmer, Anita; Koenig, Burkhard; Regensburger, Johannes; Baeumler, WolfgangPLoS One (2014), 9 (12), e111792/1-e111792/18, 18 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Photodynamic inactivation of bacteria (PIB) proves to be an addnl. method to kill pathogenic bacteria. PIB requires photosensitizer mols. that effectively generate reactive oxygen species like singlet oxygen when exposed to visible light. To allow a broad application in medicine, photosensitizers should be safe when applied in humans. Substances like vitamin B2, which are most likely safe, are known to produce singlet oxygen upon irradn. In the present study, we added pos. charges to flavin derivs. to enable attachment of these mols. to the neg. charged surface of bacteria. Two of the synthesized flavin derivs. showed a high quantum yield of singlet oxygen of approx. 75%. Multidrug resistant bacteria like MRSA (Methicillin resistant Staphylococcus aureus), EHEC (enterohemorrhagic Escherichia coli), Pseudomonas aeruginosa, and Acinetobacter baumannii were incubated with these flavin derivs. in vitro and were subsequently irradiated with visible light for seconds only. Singlet oxygen prodn. in bacteria was proved by detecting its luminescence at 1270 nm. After irradn., the no. of viable bacteria decreased up to 6 log10 steps depending on the concn. of the flavin derivs. and the light dosimetry. The bactericidal effect of PIB was independent of the bacterial type and the corresponding antibiotic resistance pattern. In contrast, the photosensitizer concn. and light parameters used for bacteria killing did not affect cell viability of human keratinocytes (therapeutic window). Multiresistant bacteria can be safely and effectively killed by a combination of modified vitamin B2 mols., oxygen and visible light, whereas normal skin cells survive. Further work will include these new photosensitizers for topical application to decolonize bacteria from skin and mucosa.48Wainwright, M.; Crossley, K. B. Methylene Blue - a Therapeutic Dye for All Seasons?. J. Chemother. 2002, 14, 431– 443, DOI: 10.1179/joc.2002.14.5.431[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XpsVyrsbc%253D&md5=090d09b1bcf57306634e09ecd6c513efMethylene blue - a therapeutic dye for all seasons?Wainwright, M.; Crossley, K. B.Journal of Chemotherapy (Firenze, Italy) (2002), 14 (5), 431-443CODEN: JCHEEU; ISSN:1120-009X. (E.I.F.T. srl)A review. Since it was first synthesized in 1876, Methylene Blue (MB) has found uses in many different areas of clin. medicine, ranging from dementia to cancer chemotherapy. In addn., MB formed the basis of antimicrobial chemotherapy - particularly in the area of antimalarials - and eventually led to the discovery of the neuroleptic drug families. More recently, the photosensitizing potential of MB and its congeners has been recognized, and these are being applied in various antimicrobial fields, esp. that of blood disinfection. The range of activities of MB is due to the combination of its simple chem. structure and facility for oxidn.-redn. reactions in situ.49Tseng, S. P.; Hung, W. C.; Chen, H. J.; Lin, Y. T.; Jiang, H. S.; Chiu, H. C.; Hsueh, P. R.; Teng, L. J.; Tsai, J. C. Effects of Toluidine Blue O (Tbo)-Photodynamic Inactivation on Community-Associated Methicillin-Resistant Staphylococcus Aureus Isolates. J. Microbiol. Immunol. Infect. 2017, 50, 46– 54, DOI: 10.1016/j.jmii.2014.12.007[Crossref], [PubMed], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1eisLk%253D&md5=562bc22fbde3d28bc63b4ee4c25a2397Effects of toluidine blue O (TBO)-photodynamic inactivation on community-associated methicillin-resistant Staphylococcus aureus isolatesTseng, Sung-Pin; Hung, Wei-Chun; Chen, Hsiao-Jan; Lin, Yu-Tzu; Jiang, Hung-Sih; Chiu, Hao-Chieh; Hsueh, Po-Ren; Teng, Lee-Jene; Tsai, Jui-ChangJournal of Microbiology, Immunology and Infection (2017), 50 (1), 46-54CODEN: JMIIFG; ISSN:1995-9133. (Elsevier Taiwan LLC)Community-assocd. methicillin-resistant Staphylococcus aureus (CA-MRSA) was recognized as a leading pathogen and has been shown to be genetically different from the health care-assocd. MRSA (HA-MRSA). Photodynamic therapy (PDT) is considered a potential alternative method for the treatment of resistant bacterial infections, but the effect of PDT on CA-MRSA is unknown. The purpose of this study was to compare the bactericidal effects of toluidine blue O (TBO) on CA-MRSA and HA-MRSA and investigate the photodynamic inactivation effects of TBO (TBO-PDI) against bacterial virulence factors.TBO-PDI effects were detd. by measuring the survival fractions for four strains and bactericidal activities for 26 CA-MRSA isolates and 26 HA-MRSA isolates. The influences of TBO-PDI on DNA fragmentation and the activities of protease, lipase, staphylococcal α-hemolysin, and enterotoxin were studied.TBO-PDI has effective bactericidal activity against both CA- and HA-MRSA. However, the bactericidal activity of TBO-PDI was significantly higher against HA-MRSA than CA-MRSA isolates. In addn., TBO-PDI treatment using a sublethal TBO concn. led to reduced prodn. of several virulence factors, including protease, lipase, staphylococcal α-hemolysin, and enterotoxin.Although TBO-PDI is slightly less effective against CA-MRSA than HA-MRSA isolates, TBO-PDI could reduce the prodn. of virulence factors at a sublethal TBO concn., which would be beneficial for treating CA-MRSA infections.50Tardivo, J. P.; Adami, F.; Correa, J. A.; Pinhal, M. A. S.; Baptista, M. S. A Clinical Trial Testing the Efficacy of PDT in Preventing Amputation in Diabetic Patients. Photodiagn. Photodyn. Ther. 2014, 11, 342– 350, DOI: 10.1016/j.pdpdt.2014.04.007[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cjhsVyjsA%253D%253D&md5=512e37c1f471177c72e63380746ace58A clinical trial testing the efficacy of PDT in preventing amputation in diabetic patientsTardivo Joao Paulo; Adami Fernando; Correa Joao Antonio; Pinhal Maria Aparecida S; Baptista Mauricio SPhotodiagnosis and photodynamic therapy (2014), 11 (3), 342-50 ISSN:.The feet of diabetic patients continue to be an unsolved problem in medicine. Uncontrolled neuropathy, ulceration and infection usually lead to amputation and presently there is no effective and reliable method that can be used to provide an efficient cure. Overall improvement in the salvage strategies, based on comprehensive pre-clinical evaluation, debridement, antibiotic therapy and follow up, has shown improvements in certain hospital settings, but the general picture for patients with diabetic foot is to have some sort of amputation, especially in underserved populations. It is clearly necessary to develop novel treatment strategies for this worldwide health problem. Photodynamic therapy (PDT) is a treatment modality that uses light to generate in situ reactive oxygen species, which can cause cell death. PDT can be used to treat several diseases, including foot infections that do not respond well to antibiotic therapy. There are several characteristics of PDT that make it potentially ideal to treat diabetic feet: the photosensitizer is non-toxic in the dark, but after illumination it becomes a very efficient antimicrobial agent with topical use, and it can regenerate small bones, such as the phalanges. However, PDT is still not used in clinical practice to treat diabetic feet. Therefore, we decided to perform a clinical study to prove that PDT is an effective method to avoid amputation of infected diabetic feet. An inexpensive PDT protocol was developed and applied to 18 patients with osteomyelitis, classified as Grade 3 on the Wagner scale. Only one of these patients suffered amputation. At least two of them were cured from resistant bacteria strains without intravenous antibiotic therapy. In the control group of 16 patients, all of them ended up suffering amputation. The rate of amputation in the PDT group was 0.029 times the rate in the control group and the difference is clearly statistically significant (p=0.002).51Graciano, T. B.; Coutinho, T. S.; Cressoni, C. B.; Freitas, C. de P.; Pierre, M. B. R.; de Lima Pereira, S. A.; Shimano, M. M.; Cristina da Cunha Frange, R.; Garcia, M. T. J. Using Chitosan Gels as a Toluidine Blue O Delivery System for Photodynamic Therapy of Buccal Cancer: In Vitro and in Vivo Studies. Photodiagn. Photodyn. Ther. 2015, 12, 98– 107, DOI: 10.1016/j.pdpdt.2014.11.003[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVSiu7jP&md5=14e5024b1db511500cf14af177627f89Using chitosan gels as a toluidine blue O delivery system for photodynamic therapy of buccal cancer: In vitro and in vivo studiesGraciano, Thierllen Barroso; Coutinho, Tatielle Soares; Cressoni, Camila Beatriz; Freitas, Cristhiane de Paula; Pierre, Maria Bernadete Riemma; de Lima Pereira, Sanivia Aparecida; Shimano, Marcos Massao; Cristina da Cunha Frange, Renata; Garcia, Maria Teresa JunqueiraPhotodiagnosis and Photodynamic Therapy (2015), 12 (1), 98-107CODEN: PPTHBF; ISSN:1572-1000. (Elsevier B.V.)Photodynamic therapy (PDT) is an emerging treatment that has demonstrated potential for the clin. treatment of buccal cancer. It is based on the photoactivation of a photosensitizer (PS) when irradiated by light at a specific wavelength. The light-excited PS generates reactive oxygen species that cause the destruction of tumor cells by apoptosis or necrosis. Toluidine Blue O (TBO) is a PS that has shown potential for PDT in cancer treatment. However, saliva and mech. activities quickly remove the PS from the surface of the buccal mucosa. Therefore, the bioavailability of PS at the surface of target tissues is reduced. The aim of this study was to evaluate the potential of chitosan (CH) gels in TBO delivery to buccal tissue. CH gels were obtained at different concns. and their physico-chem. properties (pH and rheol.), mucoadhesion, in vitro release profile, in vivo retention and in vivo efficacy by the ability to induce cell apoptosis were evaluated. CH-based mucoadhesive gels optimized the release and adherence of prepns. at the target site. Specifically, 4% (wt./wt.) CH gel showed adequate properties for buccal use, such as pH value, mucoadhesion, pseudoplastic behavior, extended release, minimal permeation and higher TBO retention by the mucosa. In vivo studies showed the potential of the gel to enhance TBO retention and induce cell apoptosis after laser irradn.4% (wt./wt.) CH based mucoadhesive gel can be explored as a TBO delivery system in the PDT of oral cancer.52Costa, A. C. B. P.; Rasteiro, V. M. C.; Pereira, C. A.; Rossoni, R. D.; Junqueira, J. C.; Jorge, A. O. C. The Effects of Rose Bengal- and Erythrosine-Mediated Photodynamic Therapy on Candida Albicans. Mycoses 2012, 55, 56– 63, DOI: 10.1111/j.1439-0507.2011.02042.x[Crossref], [PubMed], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivFOkt74%253D&md5=731f0333f2ea4e9c200fc9400a27a172The effects of rose bengal- and erythrosine-mediated photodynamic therapy on Candida albicansCosta, Anna Carolina Borges Pereira; Rasteiro, Vanessa Maria Campos; Pereira, Cristiane Aparecida; Rossoni, Rodnei Dennis; Junqueira, Juliana Campos; Jorge, Antonio Olavo CardosoMycoses (2012), 55 (1), 56-63CODEN: MYCSEU; ISSN:0933-7407. (Wiley-Blackwell)The aim of this study was to evaluate the effects of photodynamic therapy (PDT) using rose bengal or erythrosine with light emitting diode (LED) on Candida albicans planktonic cultures and biofilms. Seven C. albicans clin. strains and one std. strain (ATCC 18804) were used. Planktonic cultures and biofilms of each C. albicans strain were submitted to the following exptl. conditions: (a) treatment with rose bengal and LED (RB+L+); (b) treatment with erythrosine and LED (E+L+); and (c) control group, without LED irradn. or photosensitizer treatment (P-L-). After irradn. of the planktonic cultures and biofilms, the cultures were seeded onto Sabouraud dextrose agar (37 °C at 48 h) for counting of colony-forming units (CFU ml-1) followed by posterior ANOVA and Tukey's test analyses (P < 0.05). The biofilms were analyzed using SEM (SEM). The results revealed a significant redn. of planktonic cultures (3.45 log10 and 1.97 log10) and of biofilms (<1 log10) for cultures that were subjected to PDT mediated using either erythrosine or rose bengal, resp. The SEM data revealed that the PDT was effective in reducing and destroying of C. albicans blastoconidia and hyphae. The results show that erythrosine- and rose bengal-mediated PDT with LED irradn. is effective in treating C. albicans.53Xu, N.; Yao, M.; Farinelli, W.; Hajjarian, Z.; Wang, Y.; Redmond, R. W.; Kochevar, I. E. Light-Activated Sealing of Skin Wounds. Lasers Surg. Med. 2015, 47, 17– 29, DOI: 10.1002/lsm.22308[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MzgtF2ksg%253D%253D&md5=95faf4def4ea78fed936012e292511c2Light-activated sealing of skin woundsXu Nan; Yao Min; Farinelli William; Hajjarian Zeinab; Wang Ying; Redmond Robert W; Kochevar Irene ELasers in surgery and medicine (2015), 47 (1), 17-29 ISSN:.BACKGROUND AND OBJECTIVES: We have developed a light-activated technology for rapidly sealing skin surgical wounds called photochemical tissue bonding (PTB). The goals of this study were to evaluate parameters influencing PTB in order to optimize its clinical efficacy and to determine whether PTB can be used to seal wounds in moderately to highly pigmented skin. STUDY DESIGN/MATERIALS AND METHODS: Application of Rose Bengal (RB) followed by exposure to 532 nm was used to seal linear incisions (1.5 mm deep, 2 cm long) in lightly pigmented (Yorkshire) and darkly pigmented (Yucatan) swine skin. The force required to open the seal (the bonding strength) was measured by in situ tensiometry. Reflectance spectra, epidermal transmission spectra, and histology were used to characterize the skin. The relationships of RB concentration and fluence to bonding strength were established in Yorkshire skin. Surface temperature was measured during irradiations and cooling was used while sealing incisions in Yucatan skin. Monte Carlo simulations were carried out to estimate the effect of epidermal melanin on the power absorbed in the dermis at the incision interface. RESULTS: The lowest fluence, 25 J/cm(2), delivered at an irradiance of 0.5 W/cm(2) substantially increased the bonding strength (∼ 10-fold) compared to controls in Yorkshire swine skin. Increasing the fluence to 100 J/cm(2) enhanced bonding strength by a further 1.5-fold. Application of 0.1% RB for 2 minutes produced the greatest bonding strength using 100 J/cm(2) and limited the penetration of RB to an ∼ 50 μm band on the dermal incision wall. Reflectance spectra indicated that Yorkshire skin had minimal melanin and that Yucatan skin was a good model for highly pigmented human skin. In Yucatan skin, the bonding strength increased 1.7-fold using 0.1% RB and 200 J/cm(2) at 1.5 W/cm(2) with cooling and epinephrine. Monte Carlo simulation indicated that absorption of 532 nm light by epidermal melanin in dark skin decreased the power absorbed along the incision in the dermis by a factor of 2.7. CONCLUSIONS: These results suggest that in lightly pigmented skin the PTB treatment time can be shortened without compromising the bonding strength. Sealing incisions using PTB in moderately and highly pigmented skin will require a careful balance of irradiance and cooling.54Panzarini, E.; Inguscio, V.; Fimia, G. M.; Dini, L. Rose Bengal Acetate PhotoDynamic Therapy (RBAc-PDT) Induces Exposure and Release of Damage-Associated Molecular Patterns (DAMPs) in Human HeLa Cells. PLoS One 2014, 9, e105778, DOI: 10.1371/journal.pone.0105778[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1ygu7fK&md5=d5156eca1fe2d4a407baa75746cb2923Rose Bengal acetate photodynamic therapy (RBAc-PDT) induces exposure and release of damage-associated molecular patterns (DAMPs) in human HeLa cellsPanzarini, Elisa; Inguscio, Valentina; Fimia, Gian Maria; Dini, LucianaPLoS One (2014), 9 (8), e105778/1-e105778/12, 12 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)The new concept of Immunogenic Cell Death (ICD), assocd. with Damage Assocd. Mol. Patterns (DAMPs) exposure and/or release, is recently becoming very appealing in cancer treatment. In this context, PhotoDynamic Therapy (PDT) can give rise to ICD and to immune response upon dead cells removal. The list of PhotoSensitizers (PSs) able to induce ICD is still short and includes Photofrin, Hypericin, Foscan and 5-ALA. The goal of the present work was to investigate if Rose Bengal Acetate (RBAc), a powerful PS able to trigger apoptosis and autophagy, enables photosensitized HeLa cells to expose and/or release pivotal DAMPs, i.e. ATP, HSP70, HSP90, HMGB1, and calreticulin (CRT), that characterize ICD. We found that apoptotic HeLa cells after RBAc-PDT exposed and released, early after the treatment, high amt. of ATP, HSP70, HSP90 and CRT; the latter was distributed on the cell surface as uneven patches and co-exposed with ERp57. Conversely, autophagic HeLa cells after RBAc-PDT exposed and released HSP70, HSP90 but not CRT and ATP. Exposure and release of HSP70 and HSP90 were always higher on apoptotic than on autophagic cells. HMGB1 was released concomitantly to secondary necrosis (24 h after RBAc-PDT). Phagocytosis assay suggests that CRT is involved in removal of RBAc-PDT generated apoptotic HeLa cells. Altogether, our data suggest that RBAc has all the prerequisites (i.e. exposure and/or release of ATP, CRT, HSP70 and HSP90), that must be verified in future vaccination expts., to be considered a good PS candidate to ignite ICD. We also showed tha CRT is involved in the clearance of RBAc photokilled HeLa cells. Interestingly, RBAc-PDT is the first cancer PDT protocol able to induce the translocation of HSP90 and plasma membrane co-exposure of CRT with ERp57.55Boens, N.; Leen, V.; Dehaen, W. Fluorescent Indicators Based on Bodipy. Chem. Soc. Rev. 2012, 41, 1130– 1172, DOI: 10.1039/C1CS15132K[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xns1ygsA%253D%253D&md5=98531e55ea0e8130360135a0fa4deb59Fluorescent indicators based on BODIPYBoens, Noel; Leen, Volker; Dehaen, WimChemical Society Reviews (2012), 41 (3), 1130-1172CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. This crit. review covers the advances made using the 4-bora-3a,4a-diaza-s-indacene (BODIPY) scaffold as a fluorophore in the design, synthesis and application of fluorescent indicators for pH, metal ions, anions, biomols., reactive oxygen species, reactive nitrogen species, redox potential, chem. reactions and various phys. phenomena. The sections of the review describing the criteria for rational design of fluorescent indicators and the math. expressions for analyzing spectrophotometric and fluorometric titrns. are applicable to all fluorescent probes (206 refs.).56Kamkaew, A.; Lim, S. H.; Lee, H. B.; Kiew, L. V.; Chung, L. Y.; Burgess, K. BODIPY Dyes in Photodynamic Therapy. Chem. Soc. Rev. 2013, 42, 77– 88, DOI: 10.1039/C2CS35216H[Crossref], [PubMed], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslKrurbJ&md5=69fddf735bafa0b2b33a70835af1430fBODIPY dyes in photodynamic therapyKamkaew, Anyanee; Lim, Siang Hui; Lee, Hong Boon; Kiew, Lik Voon; Chung, Lip Yong; Burgess, KevinChemical Society Reviews (2013), 42 (1), 77-88CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. BODIPY dyes tend to be highly fluorescent, but their emissions can be attenuated by adding substituents with appropriate oxidn. potentials. Substituents like these have electrons to feed into photoexcited BODIPYs, quenching their fluorescence, thereby generating relatively long-lived triplet states. Singlet oxygen is formed when these triplet states interact with 3O2. In tissues, this causes cell damage in regions that are illuminated, and this is the basis of photodynamic therapy (PDT). The PDT agents that are currently approved for clin. use do not feature BODIPYs, but there are many reasons to believe that this situation will change. This review summarizes the attributes of BODIPY dyes for PDT, and in some related areas.57Segado, M.; Reguero, M. Mechanism of the Photochemical Process of Singlet Oxygen Production by Phenalenone. Phys. Chem. Chem. Phys. 2011, 13, 4138, DOI: 10.1039/c0cp01827a[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitVSlu7o%253D&md5=9401ff6f2fc4d817148a325d282a5959Mechanism of the photochemical process of singlet oxygen production by phenalenoneSegado, Mireia; Reguero, MarPhysical Chemistry Chemical Physics (2011), 13 (9), 4138-4148CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)Phenalenone (PN) is a very efficient singlet oxygen sensitizer in a wide range of solvents. This work uses ab initio quantum chem. calcns. (CASSCF/CASPT2 protocol) to study the mechanism for populating the triplet state of PN responsible for this reaction, the 3(π-π*) state. To describe in detail this reaction path, the singlet and triplet low-lying excited states of PN have been studied, the crit. points of the potential energy surfaces corresponding to these states located and the vertical and adiabatic energies calcd. Our results show that, after the initial population of the S2 excited state of (π-π*) character, the system undergoes an internal conversion to the 1(n-π*) state. After populating the dark S1 state, the system relaxes to the 1(n-π*) min., but rapidly populates the triplet manifold through a very efficient intersystem crossing to the 3(π-π*) state. Although the population of the min. of this triplet state is strongly favored, a conical intersection with the 3(n-π*) surface opens an internal conversion channel to this state, a path accessible only at high temps. Radiationless deactivation processes are ruled out on the basis of the high-energy barriers found for the crossings between the excited states and the ground state. Our computational results satisfactorily explain the exptl. findings and are in very good agreement with the exptl. data available. In the case of the frequency of fluorescence, this is the first time that these data have been theor. predicted in good agreement with the exptl. results.58Cieplik, F.; Späth, A.; Regensburger, J.; Gollmer, A.; Tabenski, L.; Hiller, K. A.; Bäumler, W.; Maisch, T.; Schmalz, G. Photodynamic Biofilm Inactivation by SAPYR - an Exclusive Singlet Oxygen Photosensitizer. Free Radical Biol. Med. 2013, 65, 477– 487, DOI: 10.1016/j.freeradbiomed.2013.07.031[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFylsb7P&md5=d4110d5f0ee834b47d8ae17223091d27Photodynamic biofilm inactivation by SAPYR-An exclusive singlet oxygen photosensitizerCieplik, Fabian; Spaeth, Andreas; Regensburger, Johannes; Gollmer, Anita; Tabenski, Laura; Hiller, Karl-Anton; Baeumler, Wolfgang; Maisch, Tim; Schmalz, GottfriedFree Radical Biology & Medicine (2013), 65 (), 477-487CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)Prevention and control of biofilm-growing microorganisms are serious problems in public health due to increasing resistances of some pathogens against antimicrobial drugs and the potential of these microorganisms to cause severe infections in patients. Therefore, alternative approaches that are capable of killing pathogens are needed to supplement std. treatment modalities. One alternative is the photodynamic inactivation of bacteria (PIB). The lethal effect of PIB is based on the principle that visible light activates a photosensitizer, leading to the formation of reactive oxygen species, e.g., singlet oxygen, which induces phototoxicity immediately during illumination. SAPYR is a new generation of photosensitizers. Based on a 7-perinaphthenone structure, it shows a singlet oxygen quantum yield ΦΔ of 99% and is water sol. and photostable. Moreover, it contains a pos. charge for good adherence to cell walls of pathogens. In this study, the PIB properties of SAPYR were investigated against monospecies and polyspecies biofilms formed in vitro by oral key pathogens. SAPYR showed a dual mechanism of action against biofilms: (I) it disrupts the structure of the biofilm even without illumination; (II) when irradiated, it inactivates bacteria in a polymicrobial biofilm after one single treatment with an efficacy of ≥99.99%. These results encourage further investigation on the potential of PIB using SAPYR for the treatment of localized infectious diseases.59Späth, A.; Leibl, C.; Cieplik, F.; Lehner, K.; Regensburger, J.; Hiller, K. A.; Bäumler, W.; Schmalz, G.; Maisch, T. Improving Photodynamic Inactivation of Bacteria in Dentistry: Highly Effective and Fast Killing of Oral Key Pathogens With Novel Tooth-Colored Type-II Photosensitizers. J. Med. Chem. 2014, 57, 5157– 5168, DOI: 10.1021/jm4019492[ACS Full Text], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cjnvVSjsg%253D%253D&md5=893d2358da7841c845529cf4af43d4c7Improving photodynamic inactivation of bacteria in dentistry: highly effective and fast killing of oral key pathogens with novel tooth-colored type-II photosensitizersSpath Andreas; Leibl Christoph; Cieplik Fabian; Lehner Karin; Regensburger Johannes; Hiller Karl-Anton; Baumler Wolfgang; Schmalz Gottfried; Maisch TimJournal of medicinal chemistry (2014), 57 (12), 5157-68 ISSN:.Increasing antibiotic resistances in microorganisms create serious problems in public health. This demands alternative approaches for killing pathogens to supplement standard treatment methods. Photodynamic inactivation of bacteria (PIB) uses light activated photosensitizers (PS) to generate reactive oxygen species immediately upon illumination, inducing lethal phototoxicity. Positively charged phenalen-1-one derivatives are a new generation of PS for light-mediated killing of pathogens with outstanding singlet oxygen quantum yield ΦΔ of >97%. Upon irradiation with a standard photopolymerizer light (bluephase C8, 1260 ± 50 mW/cm(2)) the PS showed high activity against the oral key pathogens Enterococcus faecalis, Actinomyces naeslundii, Streptococcus mutans, and Aggregatibacter actinomycetemcomitans. At a concentration of 10 μM, a maximum efficacy of more than 6 log10 steps (≥ 99.9999%) of bacteria killing is reached in less than 1 min (light dose 50 J/cm(2)) after one single treatment. The pyridinium substituent as positively charged moiety is especially advantageous for antimicrobial action.60Gill, M. R.; Thomas, J. A. Ruthenium(II) Polypyridyl Complexes and DNA - From Structural Probes to Cellular Imaging and Therapeutics. Chem. Soc. Rev. 2012, 41, 3179– 3192, DOI: 10.1039/c2cs15299a[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XksVOhtbY%253D&md5=0e99085c63eadb273a7532616e85b8d2Ruthenium(II) polypyridyl complexes and DNA-from structural probes to cellular imaging and therapeuticsGill, Martin R.; Thomas, Jim A.Chemical Society Reviews (2012), 41 (8), 3179-3192CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. In the last few decades, coordination complexes based on d6 metal centers and polypyridyl ligand architectures been developed as structure- and site-specific reversible DNA binding agents. Due to their attractive photophys. properties, much of this research has focused on complexes based on ruthenium(II) centers and, more recently, attention has turned to the use of these complexes in biol. contexts. As the rules that govern the cellular uptake and cellular localization of such systems are detd. they are finding numerous applications ranging from imaging to therapeutics. This review illustrates how the interdisciplinary nature of this research-which takes in synthetic chem., biophys. and in cellulo studies-makes this an exciting area in which an array of further applications are likely to emerge.61Fong, J.; Kasimova, K.; Arenas, Y.; Kaspler, P.; Lazic, S.; Mandel, A.; Lilge, L. A Novel Class of Ruthenium-Based Photosensitizers Effectively Kills In Vitro Cancer Cells and In Vivo Tumors. Photochem. Photobiol. Sci. 2015, 14, 2014– 2023, DOI: 10.1039/C4PP00438H[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitlyitL8%253D&md5=39f2dd8af513b916a677aa7c9fd009e2A novel class of ruthenium-based photosensitizers effectively kills in vitro cancer cells and in vivo tumorsFong, Jamie; Kasimova, Kamola; Arenas, Yaxal; Kaspler, Pavel; Lazic, Savo; Mandel, Arkady; Lilge, LotharPhotochemical & Photobiological Sciences (2015), 14 (11), 2014-2023CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)The photo-phys. and photo-biol. properties of two small (<2 kDa), novel Ru(II) photosensitizers (PSs) referred to as TLD1411 and TLD1433 are presented. Both PSs are highly water-sol., provide only very limited luminescence emission at 580-680 nm following excitation at 530 nm, and demonstrate high photostability with less than 50% photobleaching at radiant exposures H = 275 J cm-2 (530 nm irradn.). It was previously shown that these two photosensitizers exhibit a large singlet oxygen (1O2) quantum yield (Φ (Δ) ∼0.99 in acetonitrile). Their photon-mediated efficacy to cause cell death (λ = 530 nm, H = 45 J cm-2) was tested in vitro in colon and glioma cancer cell lines (CT26.WT, CT26.CL25, F98, and U87) and demonstrated a strong photodynamic effect with complete cell death at concns. as low as 4 and 1 μM for TLD1411 and TLD1433, resp. Notably, dark toxicity was negligible at concns. less than 25 and 10 μM for TLD1411 and TLD1433, resp. The ability of the PSs to initiate Type I photoreactions was tested by exposing PS-treated U87 cells to light under hypoxic conditions (pO2 < 0.5%), which resulted in a complete loss of the PDT effect. In vivo, the max. tolerated doses 50 (MTD50) were detd. to be 36 mg kg-1 (TLD1411) and 103 mg kg-1 (TLD1433) using the BALB/c murine model. In vivo growth delay studies in the s.c. colon adenocarcinoma CT26. WT murine model were conducted at a photosensitizer dose equal to 0.5 and 0.2 MTD50 for TLD1411 and TLD1433, resp. 4 h post PS injection, tumors were irradiated with continuous wave or pulsed light sources (λ = 525-530 nm, H = 192 J cm-2). Overall, treatment with continuous wave light demonstrated a higher tumor destruction efficacy when compared to pulsed light. TLD1433 mediated PDT resulted in statistically significant longer animal survival compared to TLD1411. Two-thirds of TLD1433-treated mice survived more than 100 days (p < 0.01) whereas TLD1411-treated mice did not survive longer than 20 days. Here we present evidence that two novel PSs have very potent photo-biol. properties and are able to cause PDT-mediated cell death in both in vitro cell culture models and in vivo tumor regression.62Angeles-Boza, A. M.; Bradley, P. M.; Fu, P. K. L.; Wicke, S. E.; Bacsa, J.; Dunbar, K. R.; Turro, C. Dna Binding and Photocleavage in Vitro by New Dirhodium(II) Dppz Complexes: Correlation to Cytotoxicity and Photocytotoxicity. Inorg. Chem. 2004, 43, 8510– 8519, DOI: 10.1021/ic049091h[ACS Full Text], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpvVGgs70%253D&md5=1d4647671e01eccb4466c37889b9534eDNA Binding and Photocleavage in Vitro by New Dirhodium(II) dppz Complexes: Correlation to Cytotoxicity and PhotocytotoxicityAngeles-Boza, Alfredo M.; Bradley, Patricia M.; Fu, Patty K.-L.; Wicke, Sara E.; Bacsa, John; Dunbar, Kim R.; Turro, ClaudiaInorganic Chemistry (2004), 43 (26), 8510-8519CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)Two new dirhodium(II) complexes possessing the intercalating dppz ligand (dppz = dipyrido[3,2-a:2',3'-c]phenazine), cis-[Rh2(μ-O2CCH3)2(dppz)(η1-O2CCH3)(CH3OH)]+ (1) and cis-[Rh2(μ-O2CCH3)2(dppz)2]2+ (2), were synthesized and characterized as potential agents for photochemotherapy. Various techniques show that 1 binds to DNA through intercalation, although some aggregation of the complex on the DNA surface is also present. In contrast, 2 does not intercalate between the DNA bases; however, strong hypochromic behavior is obsd. in the presence of DNA, which can be attributed to intermol. π-stacking of 2 enhanced by the polyanion. The apparent DNA binding consts. detd. using optical titrns. are compared to those from dialysis expts. Both complexes photocleave pUC18 plasmid in vitro under irradn. with visible light (λirr ≥ 395 nm, 15 min), resulting in the nicked, circular form. Greater photocleavage is obsd. for 1 relative to 2, which may be due to the ability of 1 to intercalate between the DNA bases. The cytotoxicity toward human skin cells (Hs-27) measured as the concn. at which 50% cell death is recorded, LC50, was found to be 135±8 μM for 2 in the dark (30 min), which is significantly lower than those of 1 (LC50 = 27±2 μM) and Rh2(O2CCH3)4 (LC50 = 15±2 μM). Irradn. of cell cultures contg. 1 and Rh2(O2CCH3)4 with visible light (400-700 nm, 30 min) has little effect on their cytotoxicity, with LC50 values of 21±3 and 13±2 μM, resp. Interestingly, a 3.4-fold increase in the toxicity of 2 is obsd. when the cell cultures are irradiated (400-700 nm, 30 min), resulting in LC50 = 39±1 μM. The greater toxicity of 1 compared to 2 in the dark may be related to the ability of the former compd. to intercalate between the DNA bases. The lower cytotoxicity of 2, together with its significantly greater photocytotoxicity, makes this complex a potential agent for photodynamic therapy (PDT). These results suggest that intercalation or strong DNA binding may not be a desirable property of a potential PDT agent.63Li, Y.; Tan, C.-P.; Zhang, W.; He, L.; Ji, L.-N.; Mao, Z.-W. Phosphorescent Iridium(III)-Bis-N-Heterocyclic Carbene Complexes as Mitochondria-Targeted Theranostic and Photodynamic Anticancer Agents. Biomaterials 2015, 39, 95– 104, DOI: 10.1016/j.biomaterials.2014.10.070[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVyhsrjM&md5=cd8df6801aa88858a2a63a39d6727384Phosphorescent iridium(III)-bis-N-heterocyclic carbene complexes as mitochondria-targeted theranostic and photodynamic anticancer agentsLi, Yi; Tan, Cai-Ping; Zhang, Wei; He, Liang; Ji, Liang-Nian; Mao, Zong-WanBiomaterials (2015), 39 (), 95-104CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Mitochondria-targeted compds. represent a promising approach to target tumors selectively and overcome resistance to current anticancer therapies. In this work, 3 cyclometalated iridium(III) complexes (1-3) contg. bis-N-heterocyclic carbene (NHC) ligands were explored as theranostic and photodynamic agents targeting mitochondria. These complexes display rich photophys. properties, which greatly facilitates the study of their intracellular fate. All 3 complexes are more cytotoxic than cisplatin against the cancer cells screened. 1-3 can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, and they can carry out theranostic functions by simultaneously inducing and monitoring the morphol. changes in mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy by initiating a cascade of events related to mitochondrial dysfunction. Addnl., they display up to 3 orders of magnitude higher cytotoxicity upon irradn. at 365 nm, which is so far the highest photocytotoxic responses reported for iridium complexes.64To, W. P.; Zou, T.; Sun, R. W. Y.; Che, C. M. Light-Induced Catalytic and Cytotoxic Properties of Phosphorescent Transition Metal Compounds with a D8 Electronic Configuration. Philos. Trans. R. Soc., A 2013, 371, 20120126, DOI: 10.1098/rsta.2012.0126[Crossref], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1yhtbvM&md5=e624be429c6231d604ddeac30715e0ccLight-induced catalytic and cytotoxic properties of phosphorescent transition metal compounds with a d8 electronic configurationTo, Wai-Pong; Zou, Taotao; Sun, Raymond Wai-Yin; Che, Chi-MingPhilosophical Transactions of the Royal Society, A: Mathematical, Physical & Engineering Sciences (2013), 371 (1995), 20120126/1-20120126/19CODEN: PTRMAD; ISSN:1364-503X. (Royal Society)Transition metal compds. are well documented to have diverse applications such as in catalysis, light-emitting materials and therapeutics. In the areas of photocatalysis and photodynamic therapy, metal compds. of heavy transition metals are highly sought after because they can give rise to triplet excited states upon photoexcitation. The long lifetimes (more than 1 μs) of the triplet states of transition metal compds. allow for bimol. reactions/processes such as energy transfer and/or electron transfer to occur. Reactions of triplet excited states of luminescent metal compds. with oxygen in cells may generate reactive oxygen species and/or induce damage to DNA, leading to cell death. This article recaps the recent findings on photochem. and phototoxic properties of luminescent platinum(II) and gold(III) compds. both from the literature and exptl. results from our group.65Senge, M. O. MTHPC - A Drug on Its Way from Second to Third Generation Photosensitizer? Photodiagnosis Photodyn. Photodiagn. Photodyn. Ther. 2012, 9, 170– 179, DOI: 10.1016/j.pdpdt.2011.10.001[Crossref], [PubMed], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xnt1yrsL8%253D&md5=b7be2c5b6039ead9fd7083848695fcc9mTHPC - A drug on its way from second to third generation photosensitizer?Senge, Mathias O.Photodiagnosis and Photodynamic Therapy (2012), 9 (2), 170-179CODEN: PPTHBF; ISSN:1572-1000. (Elsevier B.V.)A review. 5,10,15,20-Tetrakis(3-hydroxyphenyl)chlorin (mTHPC, Temoporfin) is a widely investigated second generation photosensitizer. Its initial use in soln. form (Foscan) is now complemented by nanoformulations (Fospeg, Foslip) and new chem. derivs. related to the basic hydroxyphenylporphyrin framework. Advances in formulation, chem. modifications and targeting strategies open the way for third generation photosensitizers and give an illustrative example for the developmental process of new photoactive drugs.66Anand, S.; Ortel, B. J.; Pereira, S. P.; Hasan, T.; Maytin, E. V. Biomodulatory Approaches to Photodynamic Therapy for Solid Tumors. Cancer Lett. 2012, 326, 8– 16, DOI: 10.1016/j.canlet.2012.07.026[Crossref], [PubMed], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtF2nsrzM&md5=75c600125ee50e31a7f0988f7f3a8301Biomodulatory approaches to photodynamic therapy for solid tumorsAnand, Sanjay; Ortel, Bernhard J.; Pereira, Stephen P.; Hasan, Tayyaba; Maytin, Edward V.Cancer Letters (New York, NY, United States) (2012), 326 (1), 8-16CODEN: CALEDQ; ISSN:0304-3835. (Elsevier)A review. Photodynamic Therapy (PDT) uses a photosensitizing drug in combination with visible light to kill cancer cells. PDT has an advantage over surgery or ionizing radiation because PDT can eliminate tumors without causing fibrosis or scarring. Disadvantages include the dual need for drug and light, and a generally lower efficacy for PDT vs. surgery. This mini-review describes basic principles of PDT, photosensitizers available, and aspects of tumor biol. that may provide further opportunities for treatment optimization. An emerging biomodulatory approach, using methotrexate or Vitamin D in combination with aminolevulinate-based PDT, is described. Finally, current clin. uses of PDT for solid malignancies are reviewed.67Byrne, A. T.; O’Connor, A. E.; Hall, M.; Murtagh, J.; O’Neill, K.; Curran, K. M.; Mongrain, K.; Rousseau, J. A.; Lecomte, R.; McGee, S.; Callanan, J. J.; O’Shea, D. F.; Gallagher, W. M. Vascular-Targeted Photodynamic Therapy With BF2-Chelated Tetraaryl-Azadipyrromethene Agents: A Multi-Modality Molecular Imaging Approach to Therapeutic Assessment. Br. J. Cancer 2009, 101, 1565– 1573, DOI: 10.1038/sj.bjc.6605247[Crossref], [PubMed], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlWlsr%252FJ&md5=ec41e2cfec1957b8ad6e5befb76fd68bVascular-targeted photodynamic therapy with BF2-chelated Tetraaryl-Azadipyrromethene agents: a multi-modality molecular imaging approach to therapeutic assessmentByrne, A. T.; O'Connor, A. E.; Hall, M.; Murtagh, J.; O'Neill, K.; Curran, K. M.; Mongrain, K.; Rousseau, J. A.; Lecomte, R.; McGee, S.; Callanan, J. J.; O'Shea, D. F.; Gallagher, W. M.British Journal of Cancer (2009), 101 (9), 1565-1573CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)Photodynamic therapy (PDT) is a treatment modality for a range of diseases including cancer. The BF2-chelated tetraaryl-azadipyrromethenes (ADPMs) are an emerging class of non-porphyrin PDT agent, which have previously shown excellent photochem. and photophys. properties for therapeutic application. Herein, in vivo efficacy and mechanism of action studies have been completed for the lead agent, ADMP06. A multi-modality imaging approach was employed to assess efficacy of treatment, as well as probe the mechanism of action of ADPM06-mediated PDT. Tumor ablation in 71% of animals bearing mammary tumors was achieved after delivery of 2 mg/kg-1 of ADPM06 followed immediately by light irradn. with 150 J/cm-2. The inherent fluorescence of ADPM06 was utilized to monitor organ biodistribution patterns, with fluorescence reaching baseline levels in all organs within 24 h. Mechanism of action studies were carried out using dynamic positron emission tomog. and magnetic resonance imaging techniques, which, when taken together, indicated a decrease in tumor vascular perfusion and concomitant redn. in tumor metab. over time after treatment. The encouraging treatment responses in vivo and vascular-targeting mechanism of action continue to indicate therapeutic benefit for this new class of photosensitizer.68Huang, Z.; Xu, H.; Meyers, A. D.; Musani, A. I.; Wang, L.; Tagg, R.; Barqawi, A. B.; Chen, Y. K. Photodynamic Therapy for Treatment of Solid Tumors - Potential and Technical Challenges. Technol. Cancer Res. Treat. 2008, 7 (4), 309– 320, DOI: 10.1177/153303460800700405[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFSrtbbO&md5=93dbaba5d27199d7dd69c00326727729Photodynamic therapy for treatment of solid tumors-potential and technical challengesHuang, Zheng; Xu, Heping; Meyers, Arlen D.; Musani, Ali I.; Wang, Luowei; Tagg, Randall; Barqawi, Al B.; Chen, Yang K.Technology in Cancer Research & Treatment (2008), 7 (4), 309-320CODEN: TCRTBS; ISSN:1533-0346. (Adenine Press)A review. Photodynamic therapy (PDT) involves the administration of photosensitizer followed by local illumination with visible light of specific wavelength(s). In the presence of oxygen mols., the light illumination of photosensitizer can lead to a series of photochem. reactions and consequently the generation of cytotoxic species. The quantity and location of PDT-induced cytotoxic species det. the nature and consequence of PDT. Much progress has been seen in both basic research and clin. application in recent years. Although the majority of approved PDT clin. protocols have primarily been used for the treatment of superficial lesions of both malignant and non-malignant diseases, intersititial PDT for the ablation of deep-seated solid tumors are now being investigated worldwide. The complexity of the geometry and non-homogeneity of solid tumor pose a great challenge on the implementation of minimally invasive interstitial PDT and the estn. of PDT dosimetry. This review will discuss the recent progress and tech. challenges of various forms of interstitial PDT for the treatment of parenchymal and/or stromal tissues of solid tumors.69Foote, C. S. Mechanisms of Photosensitized Oxidation. 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Materials 2013, 6, 817– 840, DOI: 10.3390/ma6030817[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlsFCku78%253D&md5=881528bb198964140a09fe5ef323f9a0Dye sensitizers for photodynamic therapyOrmond, Alexandra B.; Freeman, Harold S.Materials (2013), 6 (), 817-840CODEN: MATEG9; ISSN:1996-1944. (MDPI AG)A review. Photofrin was first approved in the 1990s as a sensitizer for use in treating cancer via photodynamic therapy (PDT). Since then a wide variety of dye sensitizers have been developed and a few have been approved for PDT treatment of skin and organ cancers and skin diseases such as acne vulgaris. Porphyrinoid derivs. and precursors have been the most successful in producing requisite singlet oxygen, with Photofrin still remaining the most efficient sensitizer (quantum yield = 0.89) and having broad food and drug administration (FDA) approval for treatment of multiple cancer types. Other porphyrinoid compds. that have received approval from US FDA and regulatory authorities in other countries include benzoporphyrin deriv. monoacid ring A (BPD-MA), meta-tetra(hydroxyphenyl)chlorin (m-THPC), N-aspartyl chlorin e6 (NPe6) and precursors to endogenous protoporphyrin IX (PpIX): 1,5-aminolevulinic acid (ALA), Me aminolevulinate (MAL), hexaminolevulinate (HAL). Although no non-porphyrin sensitizer has been approved for PDT applications, a small no. of anthraquinone, phenothiazine, xanthene, cyanine and curcuminoid sensitizers are under consideration and some are being evaluated in clin. trials. This review focuses on the nature of PDT, dye sensitizers that have been approved for use in PDT and compds. that have entered or completed clin. trials as PDT sensitizers.71Pereira, N. A. M.; Serra, A. C.; Pinho e Melo, T. M. V. D. Novel Approach to Chlorins and Bacteriochlorins: [8π+2π] Cycloaddition of Diazafulvenium Methides with Porphyrins. Eur. J. Org. Chem. 2010, 2010, 6539– 6543, DOI: 10.1002/ejoc.20100115772Forouzanfar, M. H. Global, Regional, and National Comparative Risk Assessment of 79 Behavioural, Environmental and Occupational, and Metabolic Risks or Clusters of Risks in 188 Countries, 1990–2013: A Systematic Analysis for the Global Burden of Disease Study 2013. Lancet 2015, 386, 2287– 2323, DOI: 10.1016/S0140-6736(15)00128-2[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC283hsl2qsw%253D%253D&md5=da2db569ab4ee824e6e5738b093b3874Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013Forouzanfar Mohammad H; Alexander Lily; Anderson H Ross; Bachman Victoria F; Biryukov Stan; Brauer Michael; Burnett Richard; Casey Daniel; Coates Matthew M; Cohen Aaron; Delwiche Kristen; Estep Kara; Frostad Joseph J; Astha K C; Kyu Hmwe H; Moradi-Lakeh Maziar; Ng Marie; Slepak Erica Leigh; Thomas Bernadette A; Wagner Joseph; Aasvang Gunn Marit; Abbafati Cristiana; Abbasoglu Ozgoren Ayse; Abd-Allah Foad; Abera Semaw F; Aboyans Victor; Abraham Biju; Abraham Jerry Puthenpurakal; Abubakar Ibrahim; Abu-Rmeileh Niveen M E; Aburto Tania C; Achoki Tom; Adelekan Ademola; Adofo Koranteng; Adou Arsene K; Adsuar Jose C; Afshin Ashkan; Agardh Emilie E; Al Khabouri Mazin J; Al Lami Faris H; Alam Sayed Saidul; Alasfoor Deena; Albittar Mohammed I; Alegretti Miguel A; Aleman Alicia V; Alemu Zewdie A; Alfonso-Cristancho Rafael; Alhabib Samia; Ali Raghib; Ali Mohammed K; Alla Francois; Allebeck Peter; Allen Peter J; Alsharif Ubai; Alvarez Elena; Alvis-Guzman Nelson; Amankwaa Adansi A; Amare Azmeraw T; Ameh Emmanuel A; Ameli Omid; Amini Heresh; Ammar Walid; Anderson Benjamin O; Antonio Carl Abelardo T; Anwari Palwasha; Argeseanu Cunningham Solveig; Arnlov Johan; Arsenijevic Valentina S Arsic; Artaman Al; Asghar Rana J; Assadi Reza; Atkins Lydia S; Atkinson Charles; Avila Marco A; Awuah Baffour; Badawi Alaa; Bahit Maria C; Bakfalouni Talal; Balakrishnan Kalpana; Balalla Shivanthi; Balu Ravi Kumar; Banerjee Amitava; Barber Ryan M; Barker-Collo Suzanne L; Barquera Simon; Barregard Lars; Barrero Lope H; Barrientos-Gutierrez Tonatiuh; Basto-Abreu Ana C; Basu Arindam; Basu Sanjay; Basulaiman Mohammed O; Batis Ruvalcaba Carolina; Beardsley Justin; Bedi Neeraj; Bekele Tolesa; Bell Michelle L; Benjet Corina; Bennett Derrick A; Benzian Habib; Bernabe Eduardo; Beyene Tariku J; Bhala Neeraj; Bhalla Ashish; Bhutta Zulfiqar A; Bikbov Boris; Bin Abdulhak Aref A; Blore Jed D; Blyth Fiona M; Bohensky Megan A; Bora Basara Berrak; Borges Guilherme; Bornstein Natan M; Bose Dipan; Boufous Soufiane; Bourne Rupert R; Brainin Michael; Brazinova Alexandra; Breitborde Nicholas J; Brenner Hermann; Briggs Adam D M; Broday David M; Brooks Peter M; Bruce Nigel G; Brugha Traolach S; Brunekreef Bert; Buchbinder Rachelle; Bui Linh N; Bukhman Gene; Bulloch Andrew G; Burch Michael; Burney Peter G J; Campos-Nonato Ismael R; Campuzano Julio C; Cantoral Alejandra J; Caravanos Jack; Cardenas Rosario; Cardis Elisabeth; Carpenter David O; Caso Valeria; Castaneda-Orjuela Carlos A; Castro Ruben E; Catala-Lopez Ferran; Cavalleri Fiorella; Cavlin Alanur; Chadha Vineet K; Chang Jung-Chen; Charlson Fiona J; Chen Honglei; Chen Wanqing; Chen Zhengming; Chiang Peggy P; Chimed-Ochir Odgerel; Chowdhury Rajiv; Christophi Costas A; Chuang Ting-Wu; Chugh Sumeet S; Cirillo Massimo; Classen Thomas K D; Colistro Valentina; Colomar Mercedes; Colquhoun Samantha M; Contreras Alejandra G; Cooper Cyrus; Cooperrider Kimberly; Cooper Leslie T; Coresh Josef; Courville Karen J; Criqui Michael H; Cuevas-Nasu Lucia; Damsere-Derry James; Danawi Hadi; Dandona Lalit; Dandona Rakhi; Dargan Paul I; Davis Adrian; Davitoiu Dragos V; Dayama Anand; de Castro E Filipa; De la Cruz-Gongora Vanessa; De Leo Diego; de Lima Graca; Degenhardt Louisa; del Pozo-Cruz Borja; Dellavalle Robert P; Deribe Kebede; Derrett Sarah; Des Jarlais Don C; Dessalegn Muluken; deVeber Gabrielle A; Devries Karen M; Dharmaratne Samath D; Dherani Mukesh K; Dicker Daniel; Ding Eric L; Dokova Klara; Dorsey E Ray; Driscoll Tim R; Duan Leilei; Durrani Adnan M; Ebel Beth E; Ellenbogen Richard G; Elshrek Yousef M; Endres Matthias; Ermakov Sergey P; Erskine Holly E; Eshrati Babak; Esteghamati Alireza; Fahimi Saman; Faraon Emerito Jose A; Farzadfar Farshad; Fay Derek F J; Feigin Valery L; Feigl Andrea B; Fereshtehnejad Seyed-Mohammad; Ferrari Alize J; Ferri Cleusa P; Flaxman Abraham D; Fleming Thomas D; Foigt Nataliya; Foreman Kyle J; Paleo Urbano Fra; Franklin Richard C; Gabbe Belinda; Gaffikin Lynne; Gakidou Emmanuela; Gamkrelidze Amiran; Gankpe Fortune G; Gansevoort Ron T; Garcia-Guerra Francisco A; Gasana Evariste; Geleijnse Johanna M; Gessner Bradford D; Gething Pete; Gibney Katherine B; Gillum Richard F; Ginawi Ibrahim A M; Giroud Maurice; Giussani Giorgia; Goenka Shifalika; Goginashvili Ketevan; Gomez Dantes Hector; Gona Philimon; Gonzalez de Cosio Teresita; Gonzalez-Castell Dinorah; Gotay Carolyn C; Goto Atsushi; Gouda Hebe N; Guerrant Richard L; Gugnani Harish C; Guillemin Francis; Gunnell David; Gupta Rahul; Gupta Rajeev; Gutierrez Reyna A; Hafezi-Nejad Nima; Hagan Holly; Hagstromer Maria; Halasa Yara A; Hamadeh Randah R; Hammami Mouhanad; Hankey Graeme J; Hao Yuantao; Harb Hilda L; Haregu Tilahun Nigatu; Haro Josep Maria; Havmoeller Rasmus; Hay Simon I; Hedayati Mohammad T; Heredia-Pi Ileana B; Hernandez Lucia; Heuton Kyle R; Heydarpour Pouria; Hijar Martha; Hoek Hans W; Hoffman Howard J; Hornberger John C; Hosgood H Dean; Hoy Damian G; Hsairi Mohamed; Hu Guoqing; Hu Howard; Huang Cheng; Huang John J; Hubbell Bryan J; Huiart Laetitia; Husseini Abdullatif; Iannarone Marissa L; Iburg Kim M; Idrisov Bulat T; Ikeda Nayu; Innos Kaire; Inoue Manami; Islami Farhad; Ismayilova Samaya; Jacobsen Kathryn H; Jansen Henrica A; Jarvis Deborah L; Jassal Simerjot K; Jauregui Alejandra; Jayaraman Sudha; Jeemon Panniyammakal; Jensen Paul N; Jha Vivekanand; Jiang Fan; Jiang Guohong; Jiang Ying; Jonas Jost B; Juel Knud; Kan Haidong; Kany Roseline Sidibe S; Karam Nadim E; Karch Andre; Karema Corine K; Karthikeyan Ganesan; Kaul Anil; Kawakami Norito; Kazi Dhruv S; Kemp Andrew H; Kengne Andre P; Keren Andre; Khader Yousef S; Khalifa Shams Eldin Ali Hassan; Khan Ejaz A; Khang Young-Ho; Khatibzadeh Shahab; Khonelidze Irma; Kieling Christian; Kim Daniel; Kim Sungroul; Kim Yunjin; Kimokoti Ruth W; Kinfu Yohannes; Kinge Jonas M; Kissela Brett M; Kivipelto Miia; Knibbs Luke D; Knudsen Ann Kristin; Kokubo Yoshihiro; Kose M Rifat; Kosen Soewarta; Kraemer Alexander; Kravchenko Michael; Krishnaswami Sanjay; Kromhout Hans; Ku Tiffany; Kuate Defo Barthelemy; Kucuk Bicer Burcu; Kuipers Ernst J; Kulkarni Chanda; Kulkarni Veena S; Kumar G Anil; Kwan Gene F; Lai Taavi; Lakshmana Balaji Arjun; Lalloo Ratilal; Lallukka Tea; Lam Hilton; Lan Qing; Lansingh Van C; Larson Heidi J; Larsson Anders; Laryea Dennis O; Lavados Pablo M; Lawrynowicz Alicia E; Leasher Janet L; Lee Jong-Tae; Leigh James; Leung Ricky; Levi Miriam; Li Yichong; Li Yongmei; Liang Juan; Liang Xiaofeng; Lim Stephen S; Lindsay M Patrice; Lipshultz Steven E; Liu Shiwei; Liu Yang; Lloyd Belinda K; Logroscino Giancarlo; London Stephanie J; Lopez Nancy; Lortet-Tieulent Joannie; Lotufo Paulo A; Lozano Rafael; Lunevicius Raimundas; Ma Jixiang; Ma Stefan; Machado Vasco M P; MacIntyre Michael F; Magis-Rodriguez Carlos; Mahdi Abbas A; Majdan Marek; Malekzadeh Reza; Mangalam Srikanth; Mapoma Christopher C; Marape Marape; Marcenes Wagner; Margolis David J; Margono Christopher; Marks Guy B; Martin Randall V; Marzan Melvin B; Mashal Mohammad T; Masiye Felix; Mason-Jones Amanda J; Matsushita Kunihiro; Matzopoulos Richard; Mayosi Bongani M; Mazorodze Tasara T; McKay Abigail C; McKee Martin; McLain Abigail; Meaney Peter A; Medina Catalina; Mehndiratta Man Mohan; Mejia-Rodriguez Fabiola; Mekonnen Wubegzier; Melaku Yohannes A; Meltzer Michele; Memish Ziad A; Mendoza Walter; Mensah George A; Meretoja Atte; Mhimbira Francis Apolinary; Micha Renata; Miller Ted R; Mills Edward J; Misganaw Awoke; Mishra Santosh; Mohamed Ibrahim Norlinah; Mohammad Karzan A; Mokdad Ali H; Mola Glen L; Monasta Lorenzo; Montanez Hernandez Julio C; 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Pereira David M; Perez-Padilla Rogelio; Perez-Ruiz Fernando; Perico Norberto; Perry Samuel A L; Pervaiz Aslam; Pesudovs Konrad; Peterson Carrie B; Petzold Max; Phillips Michael R; Phua Hwee Pin; Plass Dietrich; Poenaru Dan; Polanczyk Guilherme V; Polinder Suzanne; Pond Constance D; Pope C Arden; Pope Daniel; Popova Svetlana; Pourmalek Farshad; Powles John; Prabhakaran Dorairaj; Prasad Noela M; Qato Dima M; Quezada Amado D; Quistberg D Alex A; Racape Lionel; Rafay Anwar; Rahimi Kazem; Rahimi-Movaghar Vafa; Rahman Sajjad Ur; Raju Murugesan; Rakovac Ivo; Rana Saleem M; Rao Mayuree; Razavi Homie; Reddy K Srinath; Refaat Amany H; Rehm Jurgen; Remuzzi Giuseppe; Ribeiro Antonio L; Riccio Patricia M; Richardson Lee; Riederer Anne; Robinson Margaret; Roca Anna; Rodriguez Alina; Rojas-Rueda David; Romieu Isabelle; Ronfani Luca; Room Robin; Roy Nobhojit; Ruhago George M; Rushton Lesley; Sabin Nsanzimana; Sacco Ralph L; Saha Sukanta; Sahathevan Ramesh; Sahraian Mohammad Ali; Salomon Joshua A; Salvo Deborah; 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Sturua Lela; Sunguya Bruno F; Swaminathan Soumya; Swaroop Mamta; Sykes Bryan L; Tabb Karen M; Takahashi Ken; Talongwa Roberto T; Tandon Nikhil; Tanne David; Tanner Marcel; Tavakkoli Mohammad; Te Ao Braden J; Teixeira Carolina M; Tellez Rojo Martha M; Terkawi Abdullah S; Texcalac-Sangrador Jose Luis; Thackway Sarah V; Thomson Blake; Thorne-Lyman Andrew L; Thrift Amanda G; Thurston George D; Tillmann Taavi; Tobollik Myriam; Tonelli Marcello; Topouzis Fotis; Towbin Jeffrey A; Toyoshima Hideaki; Traebert Jefferson; Tran Bach X; Trasande Leonardo; Trillini Matias; Trujillo Ulises; Dimbuene Zacharie Tsala; Tsilimbaris Miltiadis; Tuzcu Emin Murat; Uchendu Uche S; Ukwaja Kingsley N; Uzun Selen B; van de Vijver Steven; Van Dingenen Rita; van Gool Coen H; van Os Jim; Varakin Yuri Y; Vasankari Tommi J; Vasconcelos Ana Maria N; Vavilala Monica S; Veerman Lennert J; Velasquez-Melendez Gustavo; Venketasubramanian N; Vijayakumar Lakshmi; Villalpando Salvador; Violante Francesco S; Vlassov Vasiliy Victorovich; Vollset Stein Emil; Wagner Gregory R; Waller Stephen G; Wallin Mitchell T; Wan Xia; Wang Haidong; Wang JianLi; Wang Linhong; Wang Wenzhi; Wang Yanping; Warouw Tati S; Watts Charlotte H; Weichenthal Scott; Weiderpass Elisabete; Weintraub Robert G; Werdecker Andrea; Wessells K Ryan; Westerman Ronny; Whiteford Harvey A; Wilkinson James D; Williams Hywel C; Williams Thomas N; Woldeyohannes Solomon M; Wolfe Charles D A; Wong John Q; Woolf Anthony D; Wright Jonathan L; Wurtz Brittany; Xu Gelin; Yan Lijing L; Yang Gonghuan; Yano Yuichiro; Ye Pengpeng; Yenesew Muluken; Yentur Gokalp K; Yip Paul; Yonemoto Naohiro; Yoon Seok-Jun; Younis Mustafa Z; Younoussi Zourkaleini; Yu Chuanhua; Zaki Maysaa E; Zhao Yong; Zheng Yingfeng; Zhou Maigeng; Zhu Jun; Zhu Shankuan; Zou Xiaonong; Zunt Joseph R; Lopez Alan D; Vos Theo; Murray Christopher JLancet (London, England) (2015), 386 (10010), 2287-323 ISSN:.BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. FINDINGS: All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8-58·5) of deaths and 41·6% (40·1-43·0) of DALYs. Risks quantified account for 87·9% (86·5-89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks. FUNDING: Bill & Melinda Gates Foundation.73Baskaran, R.; Lee, J.; Yang, S.-G. Clinical Development of Photodynamic Agents and Therapeutic Applications. Biomater. Res. 2018, 22, 1, DOI: 10.1186/s40824-018-0140-z74Lovell, J. F.; Liu, T. W. B.; Chen, J.; Zheng, G. Activatable Photosensitizers for Imaging and Therapy. Chem. Rev. 2010, 110, 2839– 2857, DOI: 10.1021/cr900236h[ACS Full Text], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1Sgu7k%253D&md5=c6bd3c7a45733ed230b04715a9477d39Activatable Photosensitizers for Imaging and TherapyLovell, Jonathan F.; Liu, Tracy W. B.; Chen, Juan; Zheng, GangChemical Reviews (Washington, DC, United States) (2010), 110 (5), 2839-2857CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review.75Derycke, A. S. L.; De Witte, P. A. M. Liposomes for Photodynamic Therapy. Adv. Drug Delivery Rev. 2004, 56, 17– 30, DOI: 10.1016/j.addr.2003.07.014[Crossref], [PubMed], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXos1Oh&md5=56dc813022f44d3fb6977962f87633e6Liposomes for photodynamic therapyDerycke, Annelies S. L.; de Witte, Peter A. M.Advanced Drug Delivery Reviews (2004), 56 (1), 17-30CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science B.V.)A review. Photodynamic therapy (PDT) is an evolving modality for the treatment of superficial tumors. The technique utilizes photosensitizing agents that are able to photochem. eradicate malignant cells. With the aim of improving the tumoritropic behavior of photosensitizers, liposomes are presently being used as carrier and delivery systems for PDT. This review covers the different liposomal strategies that are available to target photosensitizers to tumor tissue. In general, conventional liposomes carrying photosensitizers are not able to establish elevated tumor-to-normal tissue ratios, hampering their generalized use as tumoritropic carriers of photosensitizers. Conversely, liposomes with a specifically modified design, i.e. long-circulating and esp. actively targeting liposomes, stand a better chance in becoming truly tumoritropic carriers of photosensitizers. Strategies that can be employed to trigger the release of photosensitizer mols. from the liposomes are also discussed. The examd. topics are supplemented with examples of the latest developments in the field of photodynamic therapy.76Postigo, F.; Mora, M.; De Madariaga, M. A.; Nonell, S.; Sagristá, M. L. Incorporation of Hydrophobic Porphyrins Into Liposomes: Characterization and Structural Requirements. Int. J. Pharm. 2004, 278, 239– 254, DOI: 10.1016/j.ijpharm.2004.03.004[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXkslKmu7w%253D&md5=a7310c64f7a2832a3b8934e469c558bcIncorporation of hydrophobic porphyrins into liposomes: characterization and structural requirementsPostigo, F.; Mora, M.; De Madariaga, M. A.; Nonell, S.; Sagrista, M. L.International Journal of Pharmaceutics (2004), 278 (2), 239-254CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)The ability of photosensitizers to give reactive oxygenated products is considered decisive for photodynamic applications, but the hydrophobic nature of many porphyrins makes necessary to obtain suitable pharmaceutical formulations. This paper reports the structural photosensitizer features that allow the prepn. of stable liposomal formulations. Metalated and non-metalated TPPs (tetraphenylporphines) and TPyPs (tetrapyridylporphines) and different lipid/porphyrin ratios were considered in order to procure liposomal prepns. contg. porphyrin concns. adequate to necessary doses. The results show that the incorporation of porphyrins into liposomes can be related with their ability to form aggregates in a watery media. Thus, ZnTPP, which structural properties avoid the formation of aggregates, was efficiently incorporated into stable liposomes. Moreover, the efficient generation of singlet oxygen by ZnTPP liposomal suspensions has been shown. Because of this, the synthesis of hydrophobic porphyrin derived structures or other sensitizers, which do not aggregate in a watery media and with Q-bands shifted to higher λ values than ZnTPP, will be efficiently incorporated into liposomes and useful for clin. applications.77Park, W.; Park, S.-J.; Cho, S.; Shin, H.; Jung, Y.-S.; Lee, B.; Na, K.; Kim, D.-H. Intermolecular Structural Change for Thermoswitchable Polymeric Photosensitizer. J. Am. Chem. Soc. 2016, 138, 10734– 10737, DOI: 10.1021/jacs.6b04875[ACS Full Text], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlOgtrvK&md5=dec8732903f907918d0ed2a2d8f5d429Intermolecular Structural Change for Thermoswitchable Polymeric PhotosensitizerPark, Wooram; Park, Sin-Jung; Cho, Soojeong; Shin, Heejun; Jung, Young-Seok; Lee, Byeongdu; Na, Kun; Kim, Dong-HyunJournal of the American Chemical Society (2016), 138 (34), 10734-10737CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We developed a thermoswitchable polymeric photosensitizer (T-PPS) by conjugating PS (Pheophorbide-a, PPb-a) to a temp.-responsive polymer backbone of biocompatible hydroxypropyl cellulose. Self-quenched PS mols. linked in close proximity by π-π stacking in T-PPS were easily transited to an active monomeric state by the temp.-induced phase transition of polymer backbones. The temp.-responsive intermol. interaction changes of PS mols. in T-PPS were demonstrated in synchrotron small-angle X-ray scattering and UV-vis spectrophotometer anal. The T-PPS allowed switchable activation and synergistically enhanced cancer cell killing effect at the hyperthermia temp. (45 °C). Our developed T-PPS has the considerable potential not only as a new class of photomedicine in clinics but also as a biosensor based on temp. responsiveness.78Lee, C. S.; Na, K. Photochemically Triggered Cytosolic Drug Delivery Using PH-Responsive Hyaluronic Acid Nanoparticles for Light-Induced Cancer Therapy. Biomacromolecules 2014, 15, 4228– 4238, DOI: 10.1021/bm501258s[ACS Full Text], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Sju7fE&md5=60fa6709baca8b057d37ba9ad9083b93Photochemically Triggered Cytosolic Drug Delivery Using pH-Responsive Hyaluronic Acid Nanoparticles for Light-Induced Cancer TherapyLee, Chung-Sung; Na, KunBiomacromolecules (2014), 15 (11), 4228-4238CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)A photochem. triggered cytosolic drug delivery system based on combining tumor-targeting pH-responsive hyaluronic acid (HA) nanoparticles (PHANs) with anticancer therapeutics (doxorubicin; DOX) was successfully developed for light-induced cancer therapy. PHANs were prepd. through the self-assembly of a photosensitizer (PS), chlorin e6, and a pH-responsive moiety, poly(diisopropylaminoethyl) aspartamide (PDIPASP),conjugated to HA. DOX encapsulating PHANs ([email protected]) have a uniform spherical shape,a sub-100 nm size distribution and a neg. surface charge. The pH-responsiveness of PHANs leads to their disassembly due to the protonation of PDIPASP, which triggers DOX release. Competitive cellular uptake and confocal microscopy studies revealed CD44 receptor-mediated endocytosis, endosomal escape capability and efficient drug targeting. Compared to treatment with free DOX or PHANs, the combined treatment with [email protected] and spatiotemporally defined irradn. remarkably improved the anticancer efficacy both in vitro and in vivo studies. Therefore, this strategy shows promise for the photochem. triggered cytosolic drug delivery of therapeutic agents for light-induced cancer therapy.79Kim, K.; Lee, C. S.; Na, K. Light-Controlled Reactive Oxygen Species (ROS)-Producible Polymeric Micelles with Simultaneous Drug-Release Triggering and Endo/Lysosomal Escape. Chem. Commun. 2016, 52, 2839– 2842, DOI: 10.1039/C5CC09239F[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xlt1Klug%253D%253D&md5=a4bd7e31062ed97bd9dd3b9c1bc4ae8bLight-controlled reactive oxygen species (ROS)-producible polymeric micelles with simultaneous drug-release triggering and endo/lysosomal escapeKim, Kihong; Lee, Chung-Sung; Na, KunChemical Communications (Cambridge, United Kingdom) (2016), 52 (13), 2839-2842CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A doxorubicin (DOX)-loaded and light-induced ROS-producing polymeric micelle (D-LRPM), in which light triggers simultaneous DOX-release and endo/lysosomal escape, produces a powerful, spatiotemporally controllable, therapeutic efficacy for tumor treatment.80Park, S.; Park, W.; Na, K. Tumor Intracellular-Environment Responsive Materials Shielded Nano-Complexes for Highly Efficient Light-Triggered Gene Delivery without Cargo Gene Damage. Adv. Funct. Mater. 2015, 25, 3472– 3482, DOI: 10.1002/adfm.201500737[Crossref], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnvV2qurY%253D&md5=70af0df6f4b2943bb34306f25be89918Tumor intracellular-environment responsive materials shielded nano-complexes for highly efficient light-triggered gene delivery without Cargo Gene DamagePark, Sin-jung; Park, Wooram; Na, KunAdvanced Functional Materials (2015), 25 (23), 3472-3482CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)Gene therapy has great potential to bring tremendous improvement to cancer therapy. Recently, photochem. internalization (PCI) has provided the opportunity to overcome endo-lysosomal sequestration, which is one of the main bottlenecks in both gene and chemotherapeutic delivery. Despite PCI having shown great potential in gene delivery systems, it still remains difficult to perform due to the photo-oxidn. of exogenous cargo genes by reactive oxygen species (ROS) generated from activated photosensitizers (PSs). In this paper, a new type of a stable light-triggered gene delivery system is demonstrated based on endo-lysosomal pH-responsive polymeric PSs, which serve as shielding material for the polymer/gene complex. By taking advantage of the endo-lysosomal pH-sensitive de-shielding ability of the pH-responsive shielding material incorporated in the ternary gene complexes (pH-TCs), a more significant photo-triggered gene expression effect is achieved without damage to the gene from ROS. In contrast, pH-insensitive material-shielded nanocarriers cause photo-oxidn. of the payload and do not generate a notable transfection efficacy. Importantly, with the benefit of our newly developed gene delivery system, the deep penetration issue can be resolved. Finally, the light-triggered gene delivery system using pH-TCs is applied to deliver the therapeutic p53 gene in melanoma K-1735 bearing mice, showing excellent therapeutic potential for cancer.81Jo, Y.-u.; Lee, C. B.; Bae, S. K.; Na, K. Acetylated Hyaluronic Acid-Poly(L-Lactic Acid) Conjugate Nanoparticles for Inhibition of Doxorubicinol Production from Doxorubicin. Macromol. Res. 2020, 28, 67– 73, DOI: 10.1007/s13233-020-8003-6[Crossref], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsF2rt7%252FI&md5=90c11f5c8bb2bc47fed47b57f8db736fAcetylated hyaluronic acid-poly(L-lactic acid) conjugate nanoparticles for inhibition of doxorubicinol production from doxorubicinJo, Young-um; Lee, Chae Bin; Bae, Soo Kyung; Na, KunMacromolecular Research (2020), 28 (1), 67-73CODEN: MRAECT; ISSN:1598-5032. (Polymer Society of Korea)In this study, doxorubicin (DOX)-induced cardiotoxicity was overcome using cancer-recognizable DOX-loaded acetylated hyaluronic aicd-poly(L-lactic acid) (AcHA-PLLA) nanoparticles (DHPs). AcHA-PLLA was synthesized via ring opening polymn. of L-lactide with AcHA as a macroinitiator and characterized by 1H NMR and crit. micelle concn. DHPs were formed by self-assembly via dialysis, were estd. to be 160.7 ± 2.7 nm in av. diam., exhibited a slow rate release profile, and prevented DOX from being degraded in the circulation. In addn., DHPs demonstrated efficient cellular uptake into a colorectal cancer cell line (HCT-116) by CD44 receptor-mediated endocytosis, which was confirmed by in vitro cellular uptake, the competitive inhibition assay with free HA and flow cytometry. Furthermore, DHPs exhibited therapeutic efficacy against HCT-116 cells through receptor-mediated endocytosis: DHPs with free hyaluronic acid (HA) demonstrated 2-fold higher cell viability than DHPs without free HA. DHPs also inhibited doxorubicinol prodn., which induces cardiotoxicity, from DOX in vivo. The area-under-the-curve (AUC) of DOX administered as free DOX was 109.0 ± 25.0 μg min mL-1 and that from DHPs was 97.2 ± 10.2 μg min mL-1. Although these are comparable, the AUC of doxorubicinol was 1.36 ± 0.18 μg min mL-1 and 0.45 ± 0.12 μg min mL-1, with the treatment of free DOX-HCl and DHPs, resp., demonstrating the redn. of the metabolic conversion of DOX to doxorubicinol in plasma. These results indicate the role of DHPs in preventing DOX transformation into doxorubicinol, which may contribute to the reduced toxicity. DHPs are promising cancer therapeutic nanoparticles, because they are highly biocompatible and tumor-recognizable, and prevent the DOX transformation.. [Figure not available: see fulltext.].82Kim, J.; Kim, K. S.; Park, S. J.; Na, K. Vitamin Bc-Bearing Hydrophilic Photosensitizer Conjugate for Photodynamic Cancer Theranostics. Macromol. Biosci. 2015, 15, 1081– 1090, DOI: 10.1002/mabi.201500060[Crossref], [PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlsVyis7s%253D&md5=ecebda7f21c4e7e21b2088f56737a1faVitamin Bc-bearing hydrophilic photosensitizer conjugate for photodynamic cancer theranosticsKim, Jiyoung; Kim, Kyoung Sub; Park, Sin-jung; Na, KunMacromolecular Bioscience (2015), 15 (8), 1081-1090CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH & Co. KGaA)The accurate diagnosis and proper therapy for cancer are essential to improve the success rate of cancer treatment. Here, we demonstrated that the vitamin Bc-bearing hydrophilic photosensitizer conjugate folic acid-polyethylene glycol-pheophorbideA (FA-PEG-PheoA) has been synthesized for the intracellular diagnosis and photodynamic therapy of a tumor. The synthesized vitamin Bc-bearing hydrophilic photosensitizer conjugate has been characterized for the folic acid receptor expressing the ability to target tumor cells, which is facilitated by the chem. conjugation with folic acid. The vitamin Bc-bearing hydrophilic photosensitizer conjugate internalization mechanism was identified through a competitive inhibition test with free folic acid. We optimized the laser-sensitive, cytotoxicity changeable, vitamin Bc-bearing hydrophilic photosensitizer conjugate concn., which is non-cytotoxic under normal conditions and specifically cytotoxic toward cancer cells (max. 69.15%) under laser irradn. conditions used for theranostic agents. The cancer therapeutic and diagnosis effects of synthesized conjugate were confirmed in MDA-MB-231 cells and MDA-MB-231-bearing mice. As a result, the vitamin Bc-bearing hydrophilic photosensitizer conjugate exhibited a highly photodynamic therapeutic effect, which enabled the selective detection of a folic acid receptor expressing cancer using optical imaging.83Temizel, E.; Sagir, T.; Ayan, E.; Isik, S.; Ozturk, R. Delivery of Lipophilic Porphyrin by Liposome Vehicles: Preparation and Photodynamic Therapy Activity Against Cancer Cell Lines. Photodiagn. Photodyn. Ther. 2014, 11, 537– 545, DOI: 10.1016/j.pdpdt.2014.07.006[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlCis77N&md5=f7cca13fee49c59c9ec19f71c029a192Delivery of lipophilic porphyrin by liposome vehicles: Preparation and photodynamic therapy activity against cancer cell linesTemizel, Emine; Sagir, Tugba; Ayan, Esra; Isik, Sevim; Ozturk, RamazanPhotodiagnosis and Photodynamic Therapy (2014), 11 (4), 537-545CODEN: PPTHBF; ISSN:1572-1000. (Elsevier B.V.)Porphyrin photosensitizers are mostly used components in photodynamic therapy (PDT). The poor soly. of porphyrins in aq. medium is the problem to be solved for the in vivo applications. The delivery of photosensitizers to the tumor cells using liposome vehicles can help to overcome this problem. In this work, we have first functionalized the protoporphyrin IX with lipophilic oleylamine arms and encapsulated it into 1,2 dioleyl-sn-glycero-phosphatidylcholine (DOPC) liposomes. The appropriate sizes of liposomes are about 140 nm and have the characteristic Soret and Q band absorptions at 405 nm (Soret), 507 nm, 541 nm, 577 nm and 631 nm (Q bands), resp. In the photodynamic activity studies, the liposomal porphyrins were irradiated with light (375 nm, 10 mW) in the presence of cancer cell lines, HeLa and AGS. We have found that both liposomal porphyrins and oleylamine conjugated porphyrins are much more effective than PpIX. This result can be attributed to the drug delivery characteristic of the liposomes which plays effective role in endocytosis. We also found that, in AGS cells, liposomal PpIX-Ole induced apoptosis more than HeLa cells under light conditions.84Master, A.; Livingston, M.; Sen Gupta, A. Photodynamic Nanomedicine in the Treatment of Solid Tumors: Perspectives and Challenges. J. Controlled Release 2013, 168, 88– 102, DOI: 10.1016/j.jconrel.2013.02.020[Crossref], [PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXotF2gsrs%253D&md5=2e0bea8eebd6f9c739d5cc469bf638e1Photodynamic nanomedicine in the treatment of solid tumors: Perspectives and challengesMaster, Alyssa; Livingston, Megan; Sen Gupta, AnirbanJournal of Controlled Release (2013), 168 (1), 88-102CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Photodynamic therapy (PDT) is a promising treatment strategy where activation of photosensitizer drugs with specific wavelengths of light results in energy transfer cascades that ultimately yield cytotoxic reactive oxygen species which can render apoptotic and necrotic cell death. Without light the photosensitizer drugs are minimally toxic and the photoactivating light itself is non-ionizing. Therefore, harnessing this mechanism in tumors provides a safe and novel way to selectively eradicate tumor with reduced systemic toxicity and side effects on healthy tissues. For successful PDT of solid tumors, it is necessary to ensure tumor-selective delivery of the photosensitizers, as well as, the photoactivating light and to establish dosimetric correlation of light and drug parameters to PDT-induced tumor response. To this end, the nanomedicine approach provides a promising way towards enhanced control of photosensitizer biodistribution and tumor-selective delivery. In addn., refinement of nanoparticle designs can also allow incorporation of imaging agents, light delivery components and dosimetric components. This review aims at describing the current state-of-the-art regarding nanomedicine strategies in PDT, with a comprehensive narrative of the research that has been carried out in vitro and in vivo, with a discussion of the nanoformulation design aspects and a perspective on the promise and challenges of PDT regarding successful translation into clin. application.85Ogawara, K. I.; Higaki, K. Nanoparticle-Based Photodynamic Therapy: Current Status and Future Application to Improve Outcomes of Cancer Treatment. Chem. Pharm. Bull. 2017, 65, 637– 641, DOI: 10.1248/cpb.c17-00063[Crossref], [PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXis1Cltbc%253D&md5=425994e84dd63ba6bc0f9012b7b89cc0Nanoparticle-based photodynamic therapy: current status and future application to improve outcomes of cancer treatmentOgawara, Ken-ichi; Higaki, KazutakaChemical & Pharmaceutical Bulletin (2017), 65 (7), 637-641CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)A review. Photodynamic therapy (PDT) is an emerging cancer treatment that uses photosensitizers (PS), along with light to activate them, resulting in oxidn. of various biol. components in cancer tissues. However, since most potential PS are solubilized and given as aq. soln., PS is non-specifically distributed in the body, leading to the induction of various side effects in normal tissues that are exposed to daylight such as skin and eyes. To overcome the problem assocd. with non-specific in vivo disposition of PS, various approaches have been applied to develop safer dosage forms for PS with more efficient tumor delivery and lower disposition to normal tissues. Passive drug targeting to tumors with nanoparticulate formulations has been recognized as one of the potentially useful approaches to improve the poor tissue specificity of conventional cancer chemotherapy and this approach should also be applicable for more efficient tumor delivery of PS. In this review article, several issues concerning the efficacy of PDT using nanoparticle-based formulations are discussed and our recent attempts to temporally enhance the vascular permeability within tumors with photodynamic treatment for the better therapeutic outcome of nanoparticle-based therapy are introduced.86Tada, D. B.; Baptista, M. S. Photosensitizing Nanoparticles and the Modulation of ROS Generation. Front. Chem. 2015, 3, 33, DOI: 10.3389/fchem.2015.00033[Crossref], [PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mbjs1Kqsw%253D%253D&md5=b23f1943112836d0068f0d7bead9bd6cPhotosensitizing nanoparticles and the modulation of ROS generationTada Dayane B; Baptista Mauricio SFrontiers in chemistry (2015), 3 (), 33 ISSN:2296-2646.The association of PhotoSensitizer (PS) molecules with nanoparticles (NPs) forming photosensitizing NPs, has emerged as a therapeutic strategy to improve PS tumor targeting, to protect PS from deactivation reactions and to enhance both PS solubility and circulation time. Since association with NPs usually alters PS photophysical and photochemical properties, photosensitizing NPs are an important tool to modulate ROS generation. Depending on the design of the photosensitizing NP, i.e., type of PS, the NP material and the method applied for the construction of the photosensitizing NP, the deactivation routes of the excited state can be controlled, allowing the generation of either singlet oxygen or other reactive oxygen species (ROS). Controlling the type of generated ROS is desirable not only in biomedical applications, as in Photodynamic Therapy where the type of ROS affects therapeutic efficiency, but also in other technological relevant fields like energy conversion, where the electron and energy transfer processes are necessary to increase the efficiency of photoconversion cells. The current review highlights some of the recent developments in the design of Photosensitizing NPs aimed at modulating the primary photochemical events after light absorption.87Konan, Y. N.; Gurny, R.; Allémann, E. State of the Art in the Delivery of Photosensitizers for Photodynamic Therapy. J. Photochem. Photobiol., B 2002, 66, 89– 106, DOI: 10.1016/S1011-1344(01)00267-6[Crossref], [PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhvVChtL8%253D&md5=85e0a2b90a07196b695ee4a024847857State of the art in the delivery of photosensitizers for photodynamic therapyKonan, Yvette Niamien; Gurny, Robert; Allemann, EricJournal of Photochemistry and Photobiology, B: Biology (2002), 66 (2), 89-106CODEN: JPPBEG; ISSN:1011-1344. (Elsevier Science B.V.)A review. In photodynamic therapy, one of the problems limiting the use of many photosensitizers (PS) is the difficulty in prepg. pharmaceutical formulations that enable their parenteral administration. Due to their low water soly., the hydrophobic PS cannot be simply injected i.v. Different strategies, including polymer-PS conjugation or encapsulation of the drug in colloidal carriers such as oil-dispersions, liposomes and polymeric particles, have been investigated. Although these colloidal carriers tend to accumulate selectively in tumor tissues, they are rapidly taken up by the mononuclear phagocytic system. In order to reduce this undesirable uptake by phagocytic cells, long-circulating carriers that consist of surface modified carriers have been developed. Moreover, considerable effort has been directed towards using other types of carriers to improve tumor targeting and to minimize the side effects. One of the approaches is to entrap PS into the lipophilic core of low-d. lipoproteins (LDL) without altering their biol. properties. The LDL receptor pathway is an important factor in the selective accumulation of PS in tumor tissue owing to the increased no. of LDL receptors on the proliferating cell surface. Specific targeting can also be achieved by binding of mAb or specific tumor-seeking mols. to PS or by the coating of PS loaded carriers.88Paszko, E.; Ehrhardt, C.; Senge, M. O.; Kelleher, D. P.; Reynolds, J. V. Nanodrug Applications in Photodynamic Therapy. Photodiagn. Photodyn. Ther. 2011, 8, 14– 29, DOI: 10.1016/j.pdpdt.2010.12.001[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXit1Whsbo%253D&md5=b15fa05ad39cf9451d8b9e898df336feNanodrug applications in photodynamic therapyPaszko, Edyta; Ehrhardt, Carsten; Senge, Mathias O.; Kelleher, Dermot P.; Reynolds, John V.Photodiagnosis and Photodynamic Therapy (2011), 8 (1), 14-29CODEN: PPTHBF; ISSN:1572-1000. (Elsevier B.V.)A review. Photodynamic therapy (PDT) has developed over last century and is now becoming a more widely used medical tool having gained regulatory approval for the treatment of various diseases such as cancer and macular degeneration. It is a two-step technique in which the delivery of a photosensitizing drug is followed by the irradn. of light. Activated photosensitizers transfer energy to mol. oxygen which results in the generation of reactive oxygen species which in turn cause cells apoptosis or necrosis. Although this modality has significantly improved the quality of life and survival time for many cancer patients it still offers significant potential for further improvement. In addn. to the development of new PDT drugs, the use of nanosized carriers for photosensitizers is a promising approach which might improve the efficiency of photodynamic activity and which can overcome many side effects assocd. with classic photodynamic therapy. This review aims at highlighting the different types of nanomedical approaches currently used in PDT and outlines future trends and limitations of nanodelivery of photosensitizers.89Sumer, B.; Gao, J. Theranostic Nanomedicine for Cancer. Nanomedicine 2008, 3, 137– 140, DOI: 10.2217/17435889.3.2.137[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c3hvVCqtw%253D%253D&md5=7f8a40ef7881a2aad40d944e6206ba09Theranostic nanomedicine for cancerSumer Baran; Gao JinmingNanomedicine (London, England) (2008), 3 (2), 137-40 ISSN:.There is no expanded citation for this reference.90Koning, Gerben A.; Krijger, Gerard C. Targeted Multifunctional Lipid-Based Nanocarriers for Image-Guided Drug Delivery. Anti-Cancer Agents Med. Chem. 2007, 7, 425– 440, DOI: 10.2174/187152007781058613[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsV2ht7w%253D&md5=cc0cf32a780485b34373ad2151010e71Targeted multifunctional lipid-based nanocarriers for image-guided drug deliveryKoning, Gerben A.; Krijger, Gerard C.Anti-Cancer Agents in Medicinal Chemistry (2007), 7 (4), 425-440CODEN: AAMCE4; ISSN:1871-5206. (Bentham Science Publishers Ltd.)A review. Lipid-based nanocarriers have proven successful in the delivery of mainly chemotherapeutic agents, and currently they are being applied clin. in the treatment of various types of cancer. These drug delivery systems achieve increased therapeutic efficacy by altering the pharmacokinetics and biodistribution of encapsulated drugs, resulting in decreased drug toxicity and enhanced accumulation in tumor tissue. This increased accumulation is due to the relatively leaky immature vasculature of a tumor. After the clin. relevance of such drug delivery systems was demonstrated, research in this area focused on optimization, both by cell specific targeting and including controlled and triggered release concepts within the carrier. These more advanced targeted nanocarriers in general have clearly shown their potential in various animal tumor models and await clin. application. The development of targeted nanocarriers in which therapeutic and imaging agents are merged into a single carrier will certainly be of importance in the near future. Indeed, scientists active in the field of imaging (e.g. nuclear and magnetic resonance imaging) have already started to exploit nanocarriers for mol. imaging. Image-guided drug delivery using these multifunctional nanocarriers, contg. therapeutic and imaging agents, will ultimately allow for online monitoring of tumor location, tumor targeting levels, intratumoral localization and drug release kinetics prior and during radio- and/or chemotherapeutic treatment. This review describes the current status and challenges in the field of nanocarrier-aided drug delivery and drug targeting and discusses the opportunities of combining imaging probes with these drug carriers and the potential of these multifunctional lipid-based nanocarriers within image-guided drug delivery.91Batista, C. A. S.; Larson, R. G.; Kotov, N. A. Nonadditivity of Nanoparticle Interactions. Science 2015, 350, 1242477, DOI: 10.1126/science.1242477[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28zgtlyhuw%253D%253D&md5=3a751daf926f015f07a371728e0c0df0Nonadditivity of nanoparticle interactionsBatista Carlos A Silvera; Larson Ronald G; Kotov Nicholas AScience (New York, N.Y.) (2015), 350 (6257), 1242477 ISSN:.Understanding interactions between inorganic nanoparticles (NPs) is central to comprehension of self-organization processes and a wide spectrum of physical, chemical, and biological phenomena. However, quantitative description of the interparticle forces is complicated by many obstacles that are not present, or not as severe, for microsize particles (μPs). Here we analyze the sources of these difficulties and chart a course for future research. Such difficulties can be traced to the increased importance of discreteness and fluctuations around NPs (relative to μPs) and to multiscale collective effects. Although these problems can be partially overcome by modifying classical theories for colloidal interactions, such an approach fails to manage the nonadditivity of electrostatic, van der Waals, hydrophobic, and other interactions at the nanoscale. Several heuristic rules identified here can be helpful for discriminating between additive and nonadditive nanoscale systems. Further work on NP interactions would benefit from embracing NPs as strongly correlated reconfigurable systems with diverse physical elements and multiscale coupling processes, which will require new experimental and theoretical tools. Meanwhile, the similarity between the size of medium constituents and NPs makes atomic simulations of their interactions increasingly practical. Evolving experimental tools can stimulate improvement of existing force fields. New scientific opportunities for a better understanding of the electronic origin of classical interactions are converging at the scale of NPs.92Gmeiner, W. H.; Ghosh, S. Nanotechnology for Cancer Treatment. Nanotechnol. Rev. 2014, 3, 111– 122, DOI: 10.1515/ntrev-2013-0013[Crossref], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmsFWktbs%253D&md5=b4b8b2885465ab6dbc871dc61fb5ea5bNanotechnology for cancer treatmentGmeiner, William H.; Ghosh, SupratimNanotechnology Reviews (2014), 3 (2), 111-122CODEN: NRAEE8; ISSN:2191-9097. (Walter de Gruyter GmbH)A review. Nanotechnol. has the potential to increase the selectivity and potency of chem., phys., and biol. approaches for eliciting cancer cell death while minimizing collateral toxicity to nonmalignant cells. Materials on the nanoscale are increasingly being targeted to cancer cells with great specificity through both active and passive targeting. In this review, we summarize recent literature that has broken new ground in the use of nanotechnol. for cancer treatment with an emphasis on targeted drug delivery.93Elias, D. R.; Poloukhtine, A.; Popik, V.; Tsourkas, A. Effect of Ligand Density, Receptor Density, and Nanoparticle Size on Cell Targeting. Nanomedicine 2013, 9, 194– 201, DOI: 10.1016/j.nano.2012.05.015[Crossref], [PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvFCksbc%253D&md5=ee6466c57aaf7f480f68c659116ae696Effect of ligand density, receptor density, and nanoparticle size on cell targetingElias, Drew R.; Poloukhtine, Andrei; Popik, Vladimir; Tsourkas, AndrewNanomedicine (New York, NY, United States) (2013), 9 (2), 194-201CODEN: NANOBF; ISSN:1549-9634. (Elsevier)It is generally accepted that the presentation of multiple ligands on a nanoparticle (NP) surface can improve cell targeting; however, little work has been done to det. whether an optimal ligand d. exists. We have recently developed a site-specific bioconjugation strategy that allows for distinct control of ligand d. on a NP through the combined utilization of expressed protein ligation (EPL) and copper-free click chem. This EPL-Click conjugation strategy was applied to create superparamagnetic iron oxide (SPIO) NPs labeled with HER2/neu targeting affibodies at differing ligand densities. It was discovered that an intermediate ligand d. provided statistically significant improvements in cell binding in comparison with higher and lower ligand densities. This intermediate optimal ligand d. was conserved across NPs with differing hydrodynamic diams., different HER2/neu targeting ligands and also to cells with lower receptor densities. Addnl., an intermediate optimal ligand d. was also evident when NPs were labeled with folic acid. The authors of this study investigated optimal ligand d. with SPIO-based labeling and concluded that intermediate d. appears to have the most optimal labeling properties from the standpoint of its T2* shortening effect.94Sarpaki, S. Investigations into the Radiochemistry of Gallium- and Fluorine-Containing Compounds for Molecular Imaging Applications, Ph.D. Thesis, University of Bath: England, 2018.95Liu, T. W.; MacDonald, T. D.; Jin, C. S.; Gold, J. M.; Bristow, R. G.; Wilson, B. C.; Zheng, G. Inherently Multimodal Nanoparticle-Driven Tracking and Real-Time Delineation of Orthotopic Prostate Tumors and Micrometastases. ACS Nano 2013, 7, 4221– 4232, DOI: 10.1021/nn400669r[ACS Full Text], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltVOnu7o%253D&md5=2100fecc185119f0425fe3c563200a06Inherently Multimodal Nanoparticle-Driven Tracking and Real-Time Delineation of Orthotopic Prostate Tumors and MicrometastasesLiu, Tracy W.; MacDonald, Thomas D.; Jin, Cheng S.; Gold, Joseph M.; Bristow, Robert G.; Wilson, Brian C.; Zheng, GangACS Nano (2013), 7 (5), 4221-4232CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Prostate cancer is the most common cancer among men and the second cause of male cancer-related deaths. There are currently three crit. needs in prostate cancer imaging to personalize cancer treatment: (1) accurate intraprostatic imaging for multiple foci and extra-capsular extent; (2) monitoring local and systemic treatment response and predicting recurrence; and (3) more sensitive imaging of occult prostate cancer bone metastases. Recently, our lab developed porphysomes, inherently multimodal, all-org. nanoparticles with flexible and robust radiochem. Herein, we validate the first in vivo application of 64Cu-porphysomes in clin. relevant orthotopic prostate and bony metastatic cancer models. We demonstrate clear multimodal delineation of orthotopic tumors on both the macro- and the microscopic scales (using both PET and fluorescence) and sensitively detected small bony metastases (<2 mm). The unique and multifaceted properties of porphysomes offers a promising all-in-one prostate cancer imaging agent for tumor detection and treatment response/recurrence monitoring using both radionuclide- and photonic-based strategies.96Mitchell, N.; Kalber, T. L.; Cooper, M. S.; Sunassee, K.; Chalker, S. L.; Shaw, K. P.; Ordidge, K. L.; Badar, A.; Janes, S. M.; Blower, P. J.; Lythgoe, M. F.; Hailes, H. C.; Tabor, A. B. Incorporation of Paramagnetic, Fluorescent and PET/SPECT Contrast Agents Into Liposomes for Multimodal Imaging. Biomaterials 2013, 34, 1179– 1192, DOI: 10.1016/j.biomaterials.2012.09.070[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1WmsLvO&md5=2959ff9de566b6ba5b44236f1cf83b85Incorporation of paramagnetic, fluorescent and PET/SPECT contrast agents into liposomes for multimodal imagingMitchell, Nick; Kalber, Tammy L.; Cooper, Margaret S.; Sunassee, Kavitha; Chalker, Samantha L.; Shaw, Karen P.; Ordidge, Katherine L.; Badar, Adam; Janes, Samuel M.; Blower, Philip J.; Lythgoe, Mark F.; Hailes, Helen C.; Tabor, Alethea B.Biomaterials (2013), 34 (4), 1179-1192CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)A series of metal-chelating lipid conjugates has been designed and synthesized. Each member of the series bears a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) macrocycle attached to the lipid head group, using short n-ethylene glycol (n-EG) spacers of varying length. Liposomes incorporating these lipids, chelated to Gd3+, 64Cu2+, or 111In3+, and also incorporating fluorescent lipids, have been prepd., and their application in optical, magnetic resonance (MR) and single-photon emission tomog. (SPECT) imaging of cellular uptake and distribution investigated in vitro and in vivo. We have shown that these multimodal liposomes can be used as functional MR contrast agents as well as radionuclide tracers for SPECT, and that they can be optimized for each application. When shielded liposomes were formulated incorporating 50% of a lipid with a short n-EG spacer, to give nanoparticles with a shallow but even coverage of n-EG, they showed good cellular internalization in a range of tumor cells, compared to the limited cellular uptake of conventional shielded liposomes formulated with 7% 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethyleneglycol)2000] (DSPE-PEG2000). Moreover, by matching the depth of n-EG coverage to the length of the n-EG spacers of the DOTA lipids, we have shown that similar distributions and blood half lives to DSPE-PEG2000-stabilized liposomes can be achieved. The ability to tune the imaging properties and distribution of these liposomes allows for the future development of a flexible tri-modal imaging agent.97Zhang, R.; Huang, M.; Zhou, M.; Wen, X.; Huang, Q.; Li, C. Annexin A5-Functionalized Nanoparticle for Multimodal Imaging of Cell Death. Mol. Imaging 2013, 12, 7290.2012.00032, DOI: 10.2310/7290.2012.0003298Liu, T. W.; MacDonald, T. D.; Shi, J.; Wilson, B. C.; Zheng, G. Intrinsically Copper-64-Labeled Organic Nanoparticles as Radiotracers. Angew. Chem., Int. Ed. 2012, 51, 13128– 13131, DOI: 10.1002/anie.201206939[Crossref], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1OgtL%252FE&md5=213a0e3475e6210599b4b8b1f55f0e17Intrinsically Copper-64-Labeled Organic Nanoparticles as RadiotracersLiu, Tracy W.; MacDonald, Thomas D.; Shi, Jiyun; Wilson, Brian C.; Zheng, GangAngewandte Chemie, International Edition (2012), 51 (52), 13128-13131CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)An exogenous-chelator-free nanoplatform that has intrinsic capacity for use as a radiotracer is described. Copper-64-porphysomes can delineate diseased tissue in a clin. relevant orthotopic prostate cancer model.99Janib, S. M.; Moses, A. S.; MacKay, J. A. Imaging and Drug Delivery Using Theranostic Nanoparticles. Adv. Drug Delivery Rev. 2010, 62, 1052– 1063, DOI: 10.1016/j.addr.2010.08.004[Crossref], [PubMed], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVGitb7I&md5=40d00066b77a02d636c87b97ccbe404cImaging and drug delivery using theranostic nanoparticlesJanib, Siti M.; Moses, Ara S.; MacKay, J. AndrewAdvanced Drug Delivery Reviews (2010), 62 (11), 1052-1063CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Nanoparticle technologies are significantly impacting the development of both therapeutic and diagnostic agents. At the intersection between treatment and diagnosis, interest has grown in combining both paradigms into clin. effective formulations. This concept, recently coined as theranostics, is highly relevant to agents that target mol. biomarkers of disease and is expected to contribute to personalized medicine. Here the authors review state-of-the-art nanoparticles from a therapeutic and a diagnostic perspective and discuss challenges in bringing these fields together. Major classes of nanoparticles include, drug conjugates and complexes, dendrimers, vesicles, micelles, core-shell particles, microbubbles, and carbon nanotubes. Most of these formulations were described as carriers of either drugs or contrast agents. To observe these formulations and their interactions with disease, a variety of contrast agents were used, including optically active small mols., metals and metal oxides, ultrasonic contrast agents, and radionuclides. The opportunity to rapidly assess and adjust treatment to the needs of the individual offers potential advantages that will spur the development of theranostic agents.100McCarthy, J. R.; Weissleder, R. Multifunctional Magnetic Nanoparticles for Targeted Imaging and Therapy. Adv. Drug Delivery Rev. 2008, 60, 1241– 1251, DOI: 10.1016/j.addr.2008.03.014[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosVOnsr0%253D&md5=625a82ec4cc171ad24f5c6b151853cc8Multifunctional magnetic nanoparticles for targeted imaging and therapyMcCarthy, Jason R.; Weissleder, RalphAdvanced Drug Delivery Reviews (2008), 60 (11), 1241-1251CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Magnetic nanoparticles have become important tools for the imaging of prevalent diseases, such as cancer, atherosclerosis, diabetes, and others. While first generation nanoparticles were fairly nonspecific, newer generations have been targeted to specific cell types and mol. targets via affinity ligands. Commonly, these ligands emerge from phage or small mol. screens, or are based on antibodies or aptamers. Secondary reporters and combined therapeutic mols. have further opened potential clin. applications of these materials. This review summarizes some of the recent biomedical applications of these newer magnetic nanomaterials.101McCarthy, J. R. The Future of Theranostic Nanoagents. Nanomedicine 2009, 4, 693– 695, DOI: 10.2217/nnm.09.58[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1Mjgt1Sguw%253D%253D&md5=7a7b30d1133edd4d46dff3469715bfb9The future of theranostic nanoagentsMcCarthy Jason RNanomedicine (London, England) (2009), 4 (7), 693-5 ISSN:.There is no expanded citation for this reference.102Summer, D.; Grossrubatscher, L.; Petrik, M.; Michalcikova, T.; Novy, Z.; Rangger, C.; Klingler, M.; Haas, H.; Kaeopookum, P.; Von Guggenberg, E.; Haubner, R.; Decristoforo, C. Developing Targeted Hybrid Imaging Probes by Chelator Scaffolding. Bioconjugate Chem. 2017, 28, 1722– 1733, DOI: 10.1021/acs.bioconjchem.7b00182[ACS Full Text], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvFSjtL4%253D&md5=97ec9253bcecf76484667c18772177ccDeveloping Targeted Hybrid Imaging Probes by Chelator ScaffoldingSummer, Dominik; Grossrubatscher, Leo; Petrik, Milos; Michalcikova, Tereza; Novy, Zbynek; Rangger, Christine; Klingler, Maximilian; Haas, Hubertus; Kaeopookum, Piriya; von Guggenberg, Elisabeth; Haubner, Roland; Decristoforo, ClemensBioconjugate Chemistry (2017), 28 (6), 1722-1733CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Positron emission tomog. (PET) as well as optical imaging (OI) with peptide receptor targeting probes have proven their value for oncol. applications but also show restrictions depending on the clin. field of interest. Therefore, the combination of both methods, particularly in a single mol., could improve versatility in clin. routine. This proof of principle study aims to show that a chelator, Fusarinine C (FSC), can be utilized as scaffold for novel dimeric dual-modality imaging agents. Two targeting vectors (a minigastrin analog (MG11) targeting cholecystokinin-2 receptor overexpression (CCK2R) or integrin αVβ3 targeting cyclic pentapeptides (RGD)) and a near-IR fluorophore (Sulfo-Cyanine7) were conjugated to FSC. The probes were efficiently labeled with gallium-68 and in vitro expts. including detn. of logD, stability, protein binding, cell binding, internalization, and biodistribution studies as well as in vivo micro-PET/CT and optical imaging in U-87MG αVβ3- and A431-CCK2R expressing tumor xenografted mice were carried out. Novel bioconjugates showed high receptor affinity and highly specific targeting properties at both receptors. Ex vivo biodistribution and micro-PET/CT imaging studies revealed specific tumor uptake accompanied by slow blood clearance and retention in nontargeted tissues (spleen, liver, and kidneys) leading to visualization of tumors at early (30 to 120 min p.i.). Excellent contrast in corresponding optical imaging studies was achieved esp. at delayed time points (24 to 72 h p.i.). Our findings show the proof of principle of chelator scaffolding for hybrid imaging agents and demonstrate FSC being a suitable bifunctional chelator for this approach. Improvements to fine-tune pharmacokinetics are needed to translate this into a clin. setting.103Iyer, A. K.; Greish, K.; Seki, T.; Okazaki, S.; Fang, J.; Takeshita, K.; Maeda, H. Polymeric Micelles of Zinc Protoporphyrin for Tumor Targeted Delivery Based on EPR Effect and Singlet Oxygen Generation. J. Drug Target. 2007, 15, 496– 506, DOI: 10.1080/10611860701498252[Crossref], [PubMed], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosVSktL8%253D&md5=1aa4231de184724f8646d1158d7520d6Polymeric micelles of zinc protoporphyrin for tumor targeted delivery based on EPR effect and singlet oxygen generationIyer, Arun K.; Greish, Khaled; Seki, Takahiro; Okazaki, Shoko; Fang, Jun; Takeshita, Keizo; Maeda, HiroshiJournal of Drug Targeting (2007), 15 (7-8), 496-506CODEN: JDTAEH; ISSN:1061-186X. (Informa Healthcare)Polymeric micelles of zinc protoporphyrin (ZnPP) with water sol. biocompatible and amphiphilic polymer, polyethylene glycol (PEG) demonstrated unique characteristics to target tumor tissues selectively based on the enhanced permeability and retention (EPR) effect. The micellar macromol. drug of ZnPP (SMA-ZnPP and PEG-ZnPP) previously showed notable anticancer activity as a consequence of selective tumor targeting ability and its potent HO-1 inhibitory potential, resulting in suppressed biliverdin/bilirubin prodn. in tumors thereby leading to oxystress induced tumor cell killing. Furthermore, recent findings also showed that ZnPP efficiently generated reactive singlet oxygen under illumination of visible light, laser, or xenon light source, which could augment its oxystress induced cell killing abilities. In the present paper, we report the synergistic effects of light induced photosensitizing capabilities and HO-1 inhibitory potentials of these unique micelles when tested in vitro and in vivo on tumor models under localized, mild illumination conditions using a tungsten-xenon light source. The results indicate that these water sol. polymeric micelles of ZnPP portend to be promising candidates for targeted chemotherapy as well as photodynamic therapy against superficial tumors as well as solid tumors located at light penetrable depths.104Maeda, H.; Greish, K.; Fang, J. The EPR Effect and Polymeric Drugs: A Paradigm Shift for Cancer Chemotherapy in the 21st Century. Adv. Polym. Sci. 2005, 193, 103– 121, DOI: 10.1007/12_026105Cai, W.; Chen, X. Multimodality Molecular Imaging of Tumor Angiogenesis. J. Nucl. Med. 2008, 49, 113– 128, DOI: 10.2967/jnumed.107.045922[Crossref], [PubMed], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXotFahu74%253D&md5=23862c321056fbf7ff1dd5b2f011f89dMultimodality molecular imaging of tumor angiogenesisCai, Weibo; Chen, XiaoyuanJournal of Nuclear Medicine (2008), 49 (Suppl. 2), 113S-128SCODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A review. Mol. imaging is a key component of 21st-century cancer management. The vascular endothelial growth factor (VEGF)/VEGF receptor signaling pathway and integrin αvβ3, a cell adhesion mol., play pivotal roles in regulating tumor angiogenesis, the growth of new blood vessels. This review summarizes the current status of tumor angiogenesis imaging with SPECT, PET, mol. MRI, targeted ultrasound, and optical techniques. For integrin αvβ3 imaging, only nanoparticle-based probes, which truly target the tumor vasculature rather than tumor cells because of poor extravasation, are discussed. Once improvements in the in vivo stability, tumor-targeting efficacy, and pharmacokinetics of tumor angiogenesis imaging probes are made, translation to clin. applications will be crit. for the max. benefit of these novel agents. The future of tumor angiogenesis imaging lies in multimodality and nanoparticle-based approaches, imaging of protein-protein interactions, and quant. mol. imaging. Combinations of multiple modalities can yield complementary information and offer synergistic advantages over any modality alone. Nanoparticles, possessing multifunctionality and enormous flexibility, can allow for the integration of therapeutic components, targeting ligands, and multimodality imaging labels into one entity, termed "nano-medicine," for which the ideal target is tumor neovasculature. Quant. imaging of tumor angiogenesis and protein-protein interactions that modulate angiogenesis will lead to more robust and effective monitoring of personalized mol. cancer therapy. Multidisciplinary approaches and cooperative efforts from many individuals, institutions, industries, and organizations are needed to quickly translate multimodality tumor angiogenesis imaging into multiple facets of cancer management. Not limited to cancer, these novel agents can also have broad applications for many other angiogenesis-related diseases.106Haglund, E.; Seale-Goldsmith, M. M.; Leary, J. F. Design of Multifunctional Nanomedical Systems. Ann. Biomed. Eng. 2009, 37, 2048– 2063, DOI: 10.1007/s10439-009-9640-2[Crossref], [PubMed], [CAS], Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MnitlKnsg%253D%253D&md5=90b7835e0e12088f22a33fc54cb7fee6Design of multifunctional nanomedical systemsHaglund E; Seale-Goldsmith M-M; Leary J FAnnals of biomedical engineering (2009), 37 (10), 2048-63 ISSN:.Multifunctional nanoparticles hold great promise for drug/gene delivery and simultaneous diagnostics and therapeutics ("theragnostics") including use of core materials that provide in vivo imaging and opportunities for externally modulated therapeutic interventions. Multilayered nanoparticles can act as nanomedical systems with on-board molecular programming done through the chemistry of highly specialized layers to accomplish complex and potentially decision-making tasks. The targeting process itself is a multi-step process consisting of initial cell recognition through cell surface receptors, cell entry through the membrane in a manner to prevent undesired alterations of the nanomedical system, re-targeting to the appropriate sub-region of the cell where the therapeutic package can be localized, and potentially control of that therapeutic process through feedback systems using molecular biosensors. This paper describes a bionanoengineering design process in which sophisticated nanomedical platform systems can be designed for diagnosis and treatment of disease. The feasibility of most of these subsystems has been demonstrated, but the full integration of these interacting sub-components remains a challenge for the field. Specific examples of sub-components developed for specific applications are described.107Svenskaya, Y.; Parakhonskiy, B.; Haase, A.; Atkin, V.; Lukyanets, E.; Gorin, D.; Antolini, R. Anticancer Drug Delivery System Based on Calcium Carbonate Particles Loaded with a Photosensitizer. Biophys. Chem. 2013, 182, 11– 15, DOI: 10.1016/j.bpc.2013.07.006[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Cqu7zJ&md5=d18176b764ebfa127352eb7a92d6d1e8Anticancer drug delivery system based on calcium carbonate particles loaded with a photosensitizerSvenskaya, Yulia; Parakhonskiy, Bogdan; Haase, Albrecht; Atkin, Vsevolod; Lukyanets, Evgeny; Gorin, Dmitry; Antolini, RenzoBiophysical Chemistry (2013), 182 (), 11-15CODEN: BICIAZ; ISSN:0301-4622. (Elsevier B.V.)In photodynamic therapy (PDT), photosensitizers are required to arrive in high concns. at selective targets like cancer cells avoiding toxicity in healthy tissue. In this work, the authors propose the application of porous calcium carbonate carriers in the form of polycryst. vaterite for this task. The authors investigated the loading efficiency for the photosensitizer Photosens in vaterite micro- and nanocarriers. A possible release mechanism depending on the surrounding pH was studied, showing a fast degrdn. of the carriers in buffers below pH 7. These results hold out the prospect of a novel PDT drug delivery system. Variation of particle size or addnl. coatings allow custom-design of workload release curves. An intrinsic cancer-sensitivity can be expected from the pH-dependent release in the acidic microenvironment of cancer tissue.108Cheng, L.; Wang, C.; Feng, L.; Yang, K.; Liu, Z. Functional Nanomaterials for Phototherapies of Cancer. Chem. Rev. 2014, 114, 10869– 10939, DOI: 10.1021/cr400532z[ACS Full Text], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1eju7zP&md5=ef0626bcbe29036570f427034d5c8658Functional Nanomaterials for Phototherapies of CancerCheng, Liang; Wang, Chao; Feng, Liangzhu; Yang, Kai; Liu, ZhuangChemical Reviews (Washington, DC, United States) (2014), 114 (21), 10869-10939CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review.109Ding, D.; Guo, W.; Guo, C.; Sun, J.; Zheng, N.; Wang, F.; Yan, M.; Liu, S. MoO3-X Quantum Dots for Photoacoustic Imaging Guided Photothermal/Photodynamic Cancer Treatment. Nanoscale 2017, 9, 2020– 2029, DOI: 10.1039/C6NR09046J[Crossref], [PubMed], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkvVWitg%253D%253D&md5=00f6a3fd550dd12f73bd8fc33215ea61MoO3-x quantum dots for photoacoustic imaging guided photothermal/photodynamic cancer treatmentDing, Dandan; Guo, Wei; Guo, Chongshen; Sun, Jianzhe; Zheng, Nannan; Wang, Fei; Yan, Mei; Liu, ShaoqinNanoscale (2017), 9 (5), 2020-2029CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)A theranostic system of image-guided phototherapy is considered as a potential technique for cancer treatment because of the ability to integrate diagnostics and therapies together, thus enhancing accuracy and visualization during the treatment. In this work, we realized photoacoustic (PA) imaging-guided photothermal (PT)/photodynamic (PD) combined cancer treatment just via a single material, MoO3-x quantum dots (QDs). Due to their strong NIR harvesting ability, MoO3-x QDs can convert incident light into hyperthermia and sensitize the formation of singlet oxygen synchronously as evidenced by in vitro assay, hence, they can behave as both PT and PD agents effectively and act as a "dual-punch" to cancer cells. In a further study, elimination of solid tumors from HeLa-tumor bearing mice could be achieved in a MoO3-x QD mediated phototherapeutic group without obvious lesions to the major organs. In addn., the desired PT effect also makes MoO3-x QDs an exogenous PA contrast agent for in vivo live-imaging to depict tumors. Compared with previously reported theranostic systems that put several components into one system, our multifunctional agent of MoO3-x QDs is exempt from unpredictable mutual interference between components and ease of leakage of virtual components from the composited system.110Lu, K.; He, C.; Lin, W. Nanoscale Metal-Organic Framework for Highly Effective Photodynamic Therapy of Resistant Head and Neck Cancer. J. Am. Chem. Soc. 2014, 136, 16712– 16715, DOI: 10.1021/ja508679h[ACS Full Text], [CAS], Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFCisbjL&md5=8187bb3f17e2feab3346ebef74a2cbe8Nanoscale Metal-Organic Framework for Highly Effective Photodynamic Therapy of Resistant Head and Neck CancerLu, Kuangda; He, Chunbai; Lin, WenbinJournal of the American Chemical Society (2014), 136 (48), 16712-16715CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Photodynamic therapy (PDT) is an effective anticancer procedure that relies on tumor localization of a photosensitizer followed by light activation to generate cytotoxic reactive oxygen species (e.g., 1O2). Here we report the rational design of a Hf-porphyrin nanoscale metal-org. framework, DBP-UiO, as an exceptionally effective photosensitizer for PDT of resistant head and neck cancer. DBP-UiO efficiently generates 1O2 owing to site isolation of porphyrin ligands, enhanced intersystem crossing by heavy Hf centers, and facile 1O2 diffusion through porous DBP-UiO nanoplates. Consequently, DBP-UiO displayed greatly enhanced PDT efficacy both in vitro and in vivo, leading to complete tumor eradication in half of the mice receiving a single DBP-UiO dose and a single light exposure. NMOFs thus represent a new class of highly potent PDT agents and hold great promise in treating resistant cancers in the clinic.111Liu, J.; Yang, Y.; Zhu, W.; Yi, X.; Dong, Z.; Xu, X.; Chen, M.; Yang, K.; Lu, G.; Jiang, L.; Liu, Z. Nanoscale Metal-Organic Frameworks for Combined Photodynamic & Radiation Therapy in Cancer Treatment. Biomaterials 2016, 97, 1– 9, DOI: 10.1016/j.biomaterials.2016.04.034[Crossref], [PubMed], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmvFyhsbg%253D&md5=120b3e903c33466876743b04dcc8f427Nanoscale metal-organic frameworks for combined photodynamic & radiation therapy in cancer treatmentLiu, Jingjing; Yang, Yu; Zhu, Wenwen; Yi, Xuan; Dong, Ziliang; Xu, Xiaona; Chen, Meiwan; Yang, Kai; Lu, Guang; Jiang, Lixin; Liu, ZhuangBiomaterials (2016), 97 (), 1-9CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Nanoscale metal org. frameworks (NMOFs) have shown great potential in biomedicine owing to their structural/chem. diversities, high mol. loading capacities, and intrinsic biodegradability. Herein, we report the rational design of a NMOF composed by hafnium (Hf4+) and tetrakis (4-carboxyphenyl) porphyrin (TCPP). In such Hf-TCPP NMOFs, while TCPP is a photosensitizer to allow photodynamic therapy (PDT), Hf4+ with strong X-ray attenuation ability could serve as a radio-sensitizer to enhance radiotherapy (RT). Those NMOFs with polyethylene glycol (PEG) coating show efficient tumor homing upon i.v. injection, and thus could be used for in vivo combined RT & PDT, achieving a remarkable anti-tumor effect. Importantly, Hf-TCPP NMOFs show efficient clearance from the mouse body, minimizing concerns regarding their possible long-term toxicity. Our work thus presents a new concept of developing multifunctional NMOFs as a biodegradable carrier-free system, in which both metal ions and org. ligands are fully utilized to exert their therapeutic functions.112Sansaloni-Pastor, S.; Bouilloux, J.; Lange, N. The Dark Side: Photosensitizer Prodrugs. Pharmaceuticals 2019, 12 (4), 148, DOI: 10.3390/ph12040148[Crossref], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhslaltrfO&md5=a81700e60f4ecb905c932b9692611e86The dark side: photosensitizer prodrugsSansaloni-Pastor, Sara; Bouilloux, Jordan; Lange, NorbertPharmaceuticals (2019), 12 (4), 148CODEN: PHARH2; ISSN:1424-8247. (MDPI AG)A review. Photodynamic therapy (PDT) and photodiagnosis (PD) are essential approaches in the field of biophotonics. Ideally, both modalities require the selective sensitization of the targeted disease in order to avoid undesired phenomena such as the destruction of healthy tissue, skin photosensitization, or mistaken diagnosis. To a large extent, the occurrence of these incidents can be attributed to "background" accumulation in non-target tissue. Therefore, an ideal photoactive compd. should be optically silent in the absence of disease, but bright in its presence. Such requirements can be fulfilled using innovative prodrug strategies targeting disease-assocd. alterations. Here we will summarize the elaboration, characterization, and evaluation of approaches using polymeric photosensitizer prodrugs, nanoparticles, micelles, and porphysomes. Finally, we will discuss the use of 5-aminolevulinic acid and its derivs. that are selectively transformed in neoplastic cells into photoactive protoporphyrin IX.113Lovell, J. F.; Jin, C. S.; Huynh, E.; Jin, H.; Kim, C.; Rubinstein, J. L.; Chan, W. C. W.; Cao, W.; Wang, L. V.; Zheng, G. Porphysome Nanovesicles Generated by Porphyrin Bilayers for Use as Multimodal Biophotonic Contrast Agents. Nat. Mater. 2011, 10, 324– 332, DOI: 10.1038/nmat2986[Crossref], [PubMed], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjvVGjtLk%253D&md5=a49010fc6bd9ff369fd0e814ba59bdfaPorphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agentsLovell, Jonathan F.; Jin, Cheng S.; Huynh, Elizabeth; Jin, Honglin; Kim, Chulhong; Rubinstein, John L.; Chan, Warren C. W.; Cao, Weiguo; Wang, Lihong V.; Zheng, GangNature Materials (2011), 10 (4), 324-332CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)Optically active nanomaterials promise to advance a range of biophotonic techniques through nanoscale optical effects and integration of multiple imaging and therapeutic modalities. Here, we report the development of porphysomes; nanovesicles formed from self-assembled porphyrin bilayers that generated large, tunable extinction coeffs., structure-dependent fluorescence self-quenching and unique photothermal and photoacoustic properties. Porphysomes enabled the sensitive visualization of lymphatic systems using photoacoustic tomog. Near-IR fluorescence generation could be restored on dissocn., creating opportunities for low-background fluorescence imaging. As a result of their org. nature, porphysomes were enzymically biodegradable and induced minimal acute toxicity in mice with i.v. doses of 1000 mg kg-1. In a similar manner to liposomes, the large aq. core of porphysomes could be passively or actively loaded. Following systemic administration, porphysomes accumulated in tumors of xenograft-bearing mice and laser irradn. induced photothermal tumor ablation. The optical properties and biocompatibility of porphysomes demonstrate the multimodal potential of org. nanoparticles for biophotonic imaging and therapy.114Waghorn, P. A. Radiolabelled Porphyrins in Nuclear Medicine. J. Labelled Compd. Radiopharm. 2014, 57, 304– 309, DOI: 10.1002/jlcr.3166[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFGitLzN&md5=f3aad472c2742db5b76c63f7a1608e68Radiolabelled porphyrins in nuclear medicineWaghorn, Philip A.Journal of Labelled Compounds and Radiopharmaceuticals (2014), 57 (4), 304-309CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)A review. Amongst tumor-specific substances, hematoporphyrin and synthetic porphyrin derivs. have been widely investigated to identify and delineate neoplastic and malignant tissue. While the tumor localization exhibited by selected porphyrin species has been exploited through photodynamic therapy, several examples of porphyrin derivs. with varied peripheral functionality have been radiolabeled with the aim of developing porphyrin-based nuclear imaging and therapeutic agents. In this review, we look at the approaches and advances in the prepn. and uses of such radiolabeled agents for imaging and therapy. Copyright © 2013 John Wiley & Sons, Ltd.115Ng, K. K.; Takada, M.; Jin, C. C. S.; Zheng, G. Self-Sensing Porphysomes for Fluorescence-Guided Photothermal Therapy. Bioconjugate Chem. 2015, 26, 345– 351, DOI: 10.1021/bc500595d[ACS Full Text], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXktFWiug%253D%253D&md5=bea714b9dea2842eb3a59b82eb6b986fSelf-Sensing Porphysomes for Fluorescence-Guided Photothermal TherapyNg, Kenneth K.; Takada, Misa; Jin, Cheng C. S.; Zheng, GangBioconjugate Chemistry (2015), 26 (2), 345-351CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Porphysomes are highly quenched unilamellar porphyrin-lipid nanovesicles with structurally dependent photothermal properties. The high packing d. of porphyrin mols. in the lipid bilayer enables their application in photothermal therapy, whereas the partial disruption of the porphysome structure over time restores the porphyrin fluorescence and enables the fluorescence-guided photothermal ablation. This conversion is a time-dependent process and cannot be easily followed using existing anal. techniques. Here we present the design of a novel self-sensing porphysome (FRETysomes) capable of fluorescently broadcasting its structural state through Foddorster resonance energy transfer. By doping in a near-IR emitting fluorophore, it is possible to divert a small fraction of the absorbed energy toward fluorescence emission which provides information on whether the vesicle is intact or disrupted. Addn. of bacteriopheophorbide-lipid into the vesicle bilayer as a fluorescence acceptor (0.5-7.5 mol %) yields a large sepn. of 100 nm between the absorption and fluorescence bands of the nanoparticle. Furthermore, a progressive increase in FRET efficiency (14.6-72.7%) is obsd. Photothermal heating and serum stability in FRETysomes is comparable with the undoped porphysomes. The fluorescence arising from the energy transfer between the donor and acceptor dyes can be clearly visualized in vivo through hyperspectral imaging. By calcg. the ratio between the acceptor and donor fluorescence, it is possible to det. the structural fate of the nanovesicles. We observe using this technique that tumor accumulation of structurally intact porphyrin-lipid nanovesicles persists at 24 and 48 h postinjection. The development of FRETysomes offers a unique and crit. imaging tool for planning porphysome-enabled fluorescence-guided photothermal treatment, which maximizes light-induced thermal toxicity.116Allison, R. R.; Bagnato, V. S.; Sibata, C. H. Future of Oncologic Photodynamic Therapy. Future Oncol. 2010, 6, 929– 940, DOI: 10.2217/fon.10.51[Crossref], [PubMed], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXntFGitb4%253D&md5=61c462de57f6e3a2921e33fa576c7f97Future of oncologic photodynamic therapyAllison, Ron R.; Bagnato, Vanderlei S.; Sibata, Claudio H.Future Oncology (2010), 6 (6), 929-940CODEN: FOUNBN; ISSN:1479-6694. (Future Medicine Ltd.)A review. Photodynamic therapy (PDT) is a tumor-ablative and function-sparing oncol. intervention. The relative simplicity of photosensitizer application followed by light activation resulting in the cytotoxic and vasculartoxic photodynamic reaction has allowed PDT to reach a worldwide audience. With several com. available photosensitizing agents now on the market, numerous well designed clin. trials have demonstrated the efficacy of PDT on various cutaneous and deep tissue tumors. However, current photosensitizers and light sources still have a no. of limitations. Future PDT will build on those findings to allow development and refinement of more optimal therapeutic agents and illumination devices. This article reviews the current state of the art and limitations of PDT, and highlight the progress being made towards the future of oncol. PDT.117Wieder, M. E.; Hone, D. C.; Cook, M. J.; Handsley, M. M.; Gavrilovic, J.; Russell, D. A. Intracellular Photodynamic Therapy With Photosensitizer-Nanoparticle Conjugates: Cancer Therapy Using a ‘Trojan Horse.’. Photochem. Photobiol. Sci. 2006, 5, 727– 734, DOI: 10.1039/B602830F[Crossref], [PubMed], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XnslKqu7o%253D&md5=40df9e5ebd1001ef71dc457acd3cc340Intracellular photodynamic therapy with photosensitizer-nanoparticle conjugates: cancer therapy using a 'Trojan horse'Wieder, Martina E.; Hone, Duncan C.; Cook, Michael J.; Handsley, Madeleine M.; Gavrilovic, Jelena; Russell, David A.Photochemical & Photobiological Sciences (2006), 5 (8), 727-734CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)Phthalocyanine-nanoparticle conjugates have been designed and synthesized for the delivery of hydrophobic photosensitizers for photodynamic therapy (PDT) of cancer. The phthalocyanine photosensitizer stabilized gold nanoparticles have an av. diam. of 2-4 nm. The synthetic strategy interdigitates a phase transfer reagent between phthalocyanine mols. on the particle surface that solubilizes the hydrophobic photosensitizer in polar solvents enabling delivery of the nanoparticle conjugates to cells. The phthalocyanine is present in the monomeric form on the nanoparticle surface, absorbs radiation maximally at 695 nm and catalytically produces the cytotoxic species singlet oxygen with high efficiency. These properties suggest that the phthalocyanine-nanoparticle conjugates are ideally suited for PDT. In a process that can be considered as cancer therapy using a 'Trojan horse', when the nanoparticle conjugates are incubated with HeLa cells (a cervical cancer cell line), they are taken up thus delivering the phthalocyanine photosensitizer directly into the cell interior. Irradn. of the nanoparticle conjugates within the HeLa cells induced substantial cell mortality through the photodynamic prodn. of singlet oxygen. The PDT efficiency of the nanoparticle conjugates, detd. using colorimetric assay, was twice that obtained using the free phthalocyanine deriv. Following PDT with the nanoparticle conjugates, morphol. changes to the HeLa cellular structure were indicative of cell mortality via apoptosis. Further evidence of apoptosis was provided through the bioluminescent assay detection of caspase 3/7. Our results suggest that gold nanoparticle conjugates are an excellent vehicle for the delivery of surface bound hydrophobic photosensitizers for efficacious photodynamic therapy of cultured tumor cells.118Samia, A. C. S.; Chen, X.; Burda, C. Semiconductor Quantum Dots for Photodynamic Therapy. J. Am. Chem. Soc. 2003, 125, 15736– 15737, DOI: 10.1021/ja0386905[ACS Full Text], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXps1Whu70%253D&md5=e0c100daf34d18c8d9a91c2371742fc6Semiconductor quantum dots for photodynamic therapySamia, Anna C. S.; Chen, Xiaobo; Burda, ClemensJournal of the American Chemical Society (2003), 125 (51), 15736-15737CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The applicability of semiconductor QDs in photodynamic therapy (PDT) was evaluated by studying the interaction between CdSe QDs with a known silicon phthalocyanine PDT photosensitizer, Pc4. The study revealed that the QDs could be used to sensitize the PDT agent through a fluorescence resonance energy transfer (FRET) mechanism, or interact directly with mol. oxygen via a triplet energy-transfer process (TET). Both mechanisms result in the generation of reactive singlet oxygen species that can be used for PDT cancer therapy.119Jaiswal, J. K.; Mattoussi, H.; Mauro, J. M.; Simon, S. M. Long-Term Multiple Color Imaging of Live Cells Using Quantum Dot Bioconjugates. Nat. Biotechnol. 2003, 21, 47– 51, DOI: 10.1038/nbt767[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhvVyq&md5=fa97be979d4d5fae784e7239cb6a164eLong-term multiple color imaging of live cells using quantum dot bioconjugatesJaiswal, Jyoti K.; Mattoussi, Hedi; Mauro, J. Matthew; Simon, Sanford M.Nature Biotechnology (2003), 21 (1), 47-51CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)Luminescent quantum dots (QDs)-semiconductor nanocrystals-are a promising alternative to org. dyes for fluorescence-based applications. We have developed procedures for using QDs to label live cells and have demonstrated their use for long-term multicolor imaging of live cells. The two approaches presented are (i) endocytic uptake of QDs and (ii) selective labeling of cell surface proteins with QDs conjugated to antibodies. Live cells labeled using these approaches were used for long-term multicolor imaging. The cells remained stably labeled for over a week as they grew and developed. These approaches should permit the simultaneous study of multiple cells over long periods of time as they proceed through growth and development.120Lira, R. B.; Seabra, M. A. B. L.; Matos, A. L. L.; Vasconcelos, J. V.; Bezerra, D. P.; De Paula, E.; Santos, B. S.; Fontes, A. Studies on Intracellular Delivery of Carboxyl-Coated CdTe Quantum Dots Mediated by Fusogenic Liposomes. J. Mater. Chem. B 2013, 1, 4297– 4305, DOI: 10.1039/c3tb20245c[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1ent77K&md5=873ff92011ddf9ea0d7a4bedc91dbc0aStudies on intracellular delivery of carboxyl-coated CdTe quantum dots mediated by fusogenic liposomesLira, Rafael B.; Seabra, Maria A. B. L.; Matos, Anna L. L.; Vasconcelos, Jessica V.; Bezerra, Darlene P.; de Paula, Eneida; Santos, Beate S.; Fontes, AdrianaJournal of Materials Chemistry B: Materials for Biology and Medicine (2013), 1 (34), 4297-4305CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)The use of Quantum Dots (QDs) as fluorescent probes for understanding biol. functions has emerged as an advantageous alternative over application of conventional fluorescent dyes. Intracellular delivery of QDs is currently a specific field of research. When QDs are tracking a specific target in live cells, they are mostly applied for extracellular membrane labeling. In order to study intracellular mols. and structures it is necessary to deliver free QDs into the cell cytosol. In this work, we adapted the freeze and thaw method to encapsulate water dispersed carboxyl-coated CdTe QDs into liposomes of different compns., including cationic liposomes with fusogenic properties. We showed that labeled liposomes were able to fuse with live human stem cells and red blood cells in an endocytic-independent way. We followed the interactions of liposomes contg. QDs with the cells. The results were minutely discussed and showed that QDs were delivered, but they were not freely diffused in the cytosol of those cells. We believe that this approach has the potential to be applied as a general route for encapsulation and delivery of any membrane-impermeant material into living cells.121Jhonsi, M. A.; Renganathan, R. Investigations on the Photoinduced Interaction of Water Soluble Thioglycolic Acid (TGA) Capped CdTe Quantum Dots with Certain Porphyrins. J. Colloid Interface Sci. 2010, 344, 596– 602, DOI: 10.1016/j.jcis.2010.01.022[Crossref], [PubMed], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtFKjtLk%253D&md5=146638ce52524c4ca37567d8411a6e58Investigations on the photoinduced interaction of water soluble thioglycolic acid (TGA) capped CdTe quantum dots with certain porphyrinsJhonsi, M. Asha; Renganathan, R.Journal of Colloid and Interface Science (2010), 344 (2), 596-602CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)The photoinduced interaction of TGA capped CdTe quantum dots (QDs) with porphyrins such as meso-tetrakis(4-sulfonatophenyl)porphyrin [TSPP], meso-tetrakis(4-carboxyphenyl)porphyrin [TCPP], meso-tetrakis (4-N-methylpyridyl)porphyrin [TMPyP] and meso-tetraphenylporphyrin [TPP] has been studied by using absorption, steady state and time resolved fluorescence spectroscopy. The QD surface was neg. charged due to thiol capping agent contg. carboxylic group. Pos. charged TMPyP interacts with QDs through charge transfer mechanism, neg. charged porphyrins (TCPP and TSPP) interacted through energy transfer mechanism and the neutral one (TPP) does not have any interaction. The Stern-Volmer const., quenching rate const., assocn. consts., rate of electron transfer and energy transfer parameters were calcd. from the fluorescence data. Effect of mol. structure has also been studied.122Li, L.; Zhao, J. F.; Won, N.; Jin, H.; Kim, S.; Chen, J. Y. Quantum Dot - Aluminum Phthalocyanine Conjugates Perform Photodynamic Reactions to Kill Cancer Cells via Fluorescence Resonance Energy Transfer (FRET). Nanoscale Res. Lett. 2012, 7, 386, DOI: 10.1186/1556-276X-7-386[Crossref], [PubMed], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38jpt1SjsQ%253D%253D&md5=4a965385e756a43a7995148104c8a06eQuantum dot-aluminum phthalocyanine conjugates perform photodynamic reactions to kill cancer cells via fluorescence resonance energy transferLi Lei; Zhao Jin-Feng; Won Nayoun; Jin Ho; Kim Sungjee; Chen Ji-YaoNanoscale research letters (2012), 7 (1), 386 ISSN:.Sulfonated aluminum phthalocyanines (AlPcSs), commonly used photosensitizers for photodynamic therapy of cancers (PDT), were conjugated with amine-dihydrolipoic acid-coated quantum dots (QDs) by electrostatic binding, achieving 70 AlPcSs per QD. The AlPcS-QD conjugates can utilize the intense light absorptions of conjugated QDs to indirectly excite AlPcSs producing singlet oxygen via fluorescence resonance energy transfer (FRET), demonstrating a new excitation model for PDT. The AlPcS-QD conjugates easily penetrated into human nasopharyngeal carcinoma cells and carried out the FRET in cells, with efficiency around 80%. Under the irradiation of a 532-nm laser, which is at the absorption region of QDs but not fit for the absorption of AlPcSs, the cellular AlPcS-QD conjugates can destroy most cancer cells via FRET-mediated PDT, showing the potential of this new strategy for PDT.123Rakovich, A.; Savateeva, D.; Rakovich, T.; Donegan, J. F.; Rakovich, Y. P.; Kelly, V.; Lesnyak, V.; Eychmüller, A. CdTe Quantum Dot/Dye Hybrid System as Photosensitizer for Photodynamic Therapy. Nanoscale Res. Lett. 2010, 5, 753– 760, DOI: 10.1007/s11671-010-9553-x[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkvFSmsrg%253D&md5=8ad8265f7fc4dbd95fab73e576142b15CdTe quantum dot/dye hybrid system as photosensitizer for photodynamic therapyRakovich, Aliaksandra; Savateeva, Diana; Rakovich, Tatsiana; Donegan, John F.; Rakovich, Yury P.; Kelly, Vincent; Lesnyak, Vladimir; Eychmuller, AlexanderNanoscale Research Letters (2010), 5 (4), 753-760CODEN: NRLAAD; ISSN:1556-276X. (Springer)We have studied the photodynamic properties of novel CdTe quantum dots - methylene blue hybrid photosensitizer. Absorption spectroscopy, photoluminescence spectroscopy, and fluorescence lifetime imaging of this system reveal efficient charge transfer between nanocrystals and the methylene blue dye. Near-IR photoluminescence measurements provide evidence for an increased efficiency of singlet oxygen prodn. by the methylene blue dye. In vitro studies on the growth of HepG2 and HeLa cancerous cells were also performed, they point toward an improvement in the cell kill efficiency for the methylene blue-semiconductor nanocrystals hybrid system.124Tsay, J. M.; Trzoss, M.; Shi, L.; Kong, X.; Selke, M.; Jung, M. E.; Weiss, S. Singlet Oxygen Production by Peptide-Coated Quantum Dot-Photosensitizer Conjugates. J. Am. Chem. Soc. 2007, 129, 6865– 6871, DOI: 10.1021/ja070713i[ACS Full Text], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkvVClur4%253D&md5=10abb71383dcfd2921547eb262eade8eSinglet Oxygen Production by Peptide-Coated Quantum Dot-Photosensitizer ConjugatesTsay, James M.; Trzoss, Michael; Shi, Lixin; Kong, Xiangxu; Selke, Matthias; Jung, Michael E.; Weiss, ShimonJournal of the American Chemical Society (2007), 129 (21), 6865-6871CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Peptide-coated quantum dot-photosensitizer conjugates were developed using novel covalent conjugation strategies on peptides which overcoat quantum dots (QDs). Rose bengal and chlorin e6, photosensitizers (PSs) that generate singlet oxygen in high yield, were covalently attached to phytochelatin-related peptides. The photosensitizer-peptide conjugates were subsequently used to overcoat green- and red-emitting CdSe/CdS/ZnS nanocrystals. Generation of singlet oxygen could be achieved via indirect excitation through F.ovrddot.orster (fluorescence) resonance energy transfer (FRET) from the nanocrystals to PSs, or by direct excitation of the PSs. In the latter case, by using two color excitations, the conjugate could be simultaneously used for fluorescence imaging and singlet oxygen generation. Singlet oxygen quantum yields as high as 0.31 were achieved using 532-nm excitation wavelengths.125Wen, Y. N.; Song, W. S.; An, L. M.; Liu, Y. Q.; Wang, Y. H.; Yang, Y. Q. Activation of Porphyrin Photosensitizers by Semiconductor Quantum Dots via Two-Photon Excitation. Appl. Phys. Lett. 2009, 95, 143702, DOI: 10.1063/1.3243979[Crossref], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1Cns7vL&md5=de1a09eeb6b7e79d0bfb0525884526e5Activation of porphyrin photosensitizers by semiconductor quantum dots via two-photon excitationWen, Ya-Nan; Song, Wei-Si; An, Li-Min; Liu, Yu-Qiang; Wang, Ying-Hui; Yang, Yan-QiangApplied Physics Letters (2009), 95 (14), 143702/1-143702/3CODEN: APPLAB; ISSN:0003-6951. (American Institute of Physics)Energy transfer from water-sol. quantum dots (QDs) to porphyrinlike sensitizers is studied by time-resolved spectroscopy of two-photon excitation with femtosecond laser pulses. Evident transfer results are obsd. Electron exchange is found to be the dominant transfer mechanism. Relative intensity change between excitonic and trapping emission implies that nonradiative energy transfer occurs through the trapping state of QDs, which presents a way of raising energy transfer efficiency in this type of donor-acceptor pairs. This study underlines the potential of QD-porphyrin model system for applications in two-photon excitation photodynamic therapy. (c) 2009 American Institute of Physics.126Chen, J. Y.; Lee, Y. M.; Zhao, D.; Mak, N. K.; Wong, R. N. S.; Chan, W. H.; Cheung, N. H. Quantum Dot-Mediated Photoproduction of Reactive Oxygen Species for Cancer Cell Annihilation. Photochem. Photobiol. 2010, 86, 431– 437, DOI: 10.1111/j.1751-1097.2009.00652.x[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXotFGqtbg%253D&md5=4800f7186be5a66809b9b85acd023072Quantum dot-mediated photoproduction of reactive oxygen species for cancer cell annihilationChen, Ji-Yao; Lee, Yee-Man; Zhao, Dan; Mak, Nai-Ki; Wong, Ricky Ngok-Shun; Chan, Wing-Hong; Cheung, Nai-HoPhotochemistry and Photobiology (2010), 86 (2), 431-437CODEN: PHCBAP; ISSN:0031-8655. (Wiley-Blackwell)While semiconductor quantum dots produce little singlet oxygen, they may undergo Type I photoreactions to produce other reactive oxygen species (ROS) to kill cells. CdTe quantum dots coated with thioglycolic acid were used to test that possibility. Some thiol ligands were purposely removed to regenerate the surface electron traps that were passivated by the ligand. This allowed photoinduced electrons to dwell on the surface long enough to be gathered by nearby oxygen mols. to produce ROS. The photocytotoxicity of these quantum dots was tested on nasopharyngeal carcinoma cells. Photokilling was shown to be drug and light dose dependent. Using 0.6 μM quantum dots for incubation and 4.8 J cm-2 for irradn., about 80% of the cells were annihilated. These quantum dots promised to be potent sensitizers for photoannihilation of cancer cells.127Wang, R. gui; Zhao, M. yao; Deng, D.; Ye, X.; Zhang, F.; Chen, H.; Kong, J. lie An Intelligent and Biocompatible Photosensitizer Conjugated Silicon Quantum Dots-MnO2 Nanosystem for Fluorescence Imaging-Guided Efficient Photodynamic Therapy. J. Mater. Chem. B 2018, 6, 4592– 4601, DOI: 10.1039/C8TB00931G[Crossref], [PubMed], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFGgtL7N&md5=3b97c69421eba41ee77e79de96f4479cAn intelligent and biocompatible photosensitizer conjugated silicon quantum dots-MnO2 nanosystem for fluorescence imaging-guided efficient photodynamic therapyWang, Rong-gui; Zhao, Meng-yao; Deng, Di; Ye, Xin; Zhang, Fan; Chen, Hui; Kong, Ji-lieJournal of Materials Chemistry B: Materials for Biology and Medicine (2018), 6 (28), 4592-4601CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)Photodynamic therapy (PDT) has been widely applied in cancer treatment due to minimal invasion, negligible side effects and specific tumor ablation. However, the treatment efficiency has been hindered by hypoxia in solid tumors, hydrophobic photosensitizers and their real time tracking. In this paper, we constructed an intelligent and biocompatible bovine serum albumin (BSA)-Ce6-Si QDs-MnO2 (BCSM NPs) nanocomplex as a pH/H2O2 responsive photosensitizer nanocarrier to modulate tumor hypoxia for fluorescence imaging-guided efficient PDT. This versatile nanosystem not only enhanced the loading capacity of the photosensitizer and the formation of cytotoxic singlet oxygen (1O2) owing to the intelligent prodn. of oxygen catalyzed by MnO2 from the endogenous H2O2, but also performed as a dual functional fluorescence and Magnetic Resonance imaging (MRI) probe. In vivo expts. in nude mice further confirmed that BCSM NPs significantly inhibited the growth of HeLa bearing-tumors compared to free Ce6. The results highlight the great potentail of multifunctional BCSM NPs for in vivo imaging as well as enhancing the photodynamic therapy efficiency.128Biju, V.; Itoh, T.; Ishikawa, M. Delivering Quantum Dots to Cells: Bioconjugated Quantum Dots for Targeted and Nonspecific Extracellular and Intracellular Imaging. Chem. Soc. Rev. 2010, 39, 3031– 3056, DOI: 10.1039/b926512k[Crossref], [PubMed], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXptFygs7c%253D&md5=44314b2f8c76d4da56b63ceb1dc3a60aDelivering quantum dots to cells: bioconjugated quantum dots for targeted and nonspecific extracellular and intracellular imagingBiju, Vasudevanpillai; Itoh, Tamitake; Ishikawa, MitsuruChemical Society Reviews (2010), 39 (8), 3031-3056CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Bioconjugated nanomaterials offer endless opportunities to advance both nanobiotechnol. and biomedical technol. In this regard, semiconductor nanoparticles, also called quantum dots, are of particular interest for multimodal, multifunctional and multiplexed imaging of biomols., cells, tissues and animals. The unique optical properties, such as size-dependent tunable absorption and emission in the visible and NIR regions, narrow emission and broad absorption bands, high photoluminescence quantum yields, large one- and multi-photon absorption cross-sections, and exceptional photostability are the advantages of quantum dots. Multimodal imaging probes are developed by interfacing the unique optical properties of quantum dots with magnetic or radioactive materials. Besides, cryst. structure of quantum dots adds scope for high-contrast x-ray and TEM imaging. Yet another unique feature of a quantum dot is its spacious and flexible surface which is promising to integrate multiple ligands and antibodies and construct multi-functional probes for bioimaging. In this crit. review, the authors will summarize recent advancements in the prepn. of biocompatible quantum dots, bioconjugation of quantum dots, and applications of quantum dots and their bioconjugates for targeted and nonspecific imaging of extracellular and intracellular proteins, organelles and functions (181 refs.).129Viana, O. S.; Ribeiro, M. S.; Fontes, A.; Santos, B. S. Quantum Dots in Photodynamic Therapy. In Oxidative Stress in Applied Basic Research and Clinical Practice; Springer International Publishing: Switzerland, 2016; pp 525– 539.130Din, F. U.; Aman, W.; Ullah, I.; Qureshi, O. S.; Mustapha, O.; Shafique, S.; Zeb, A. Effective Use of Nanocarriers as Drug Delivery Systems for the Treatment of Selected Tumors. Int. J. Nanomed. 2017, 12, 7291– 7309, DOI: 10.2147/IJN.S146315[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7hslOjtQ%253D%253D&md5=db75f3b773624ea769aedb9b65997be8Effective use of nanocarriers as drug delivery systems for the treatment of selected tumorsDin Fakhar Ud; Aman Waqar; Ullah Izhar; Qureshi Omer Salman; Mustapha Omer; Shafique Shumaila; Zeb AlamInternational journal of nanomedicine (2017), 12 (), 7291-7309 ISSN:.Nanotechnology has recently gained increased attention for its capability to effectively diagnose and treat various tumors. Nanocarriers have been used to circumvent the problems associated with conventional antitumor drug delivery systems, including their nonspecificity, severe side effects, burst release and damaging the normal cells. Nanocarriers improve the bioavailability and therapeutic efficiency of antitumor drugs, while providing preferential accumulation at the target site. A number of nanocarriers have been developed; however, only a few of them are clinically approved for the delivery of antitumor drugs for their intended actions at the targeted sites. The present review is divided into three main parts: first part presents introduction of various nanocarriers and their relevance in the delivery of anticancer drugs, second part encompasses targeting mechanisms and surface functionalization on nanocarriers and third part covers the description of selected tumors, including breast, lungs, colorectal and pancreatic tumors, and applications of relative nanocarriers in these tumors. This review increases the understanding of tumor treatment with the promising use of nanotechnology.131Lombardo, D.; Kiselev, M. A.; Caccamo, M. T. Smart Nanoparticles for Drug Delivery Application: Development of Versatile Nanocarrier Platforms in Biotechnology and Nanomedicine. J. Nanomater. 2019, 2019, 1, DOI: 10.1155/2019/3702518132Singh, R.; Lillard, J. W. Nanoparticle-Based Targeted Drug Delivery. Exp. Mol. Pathol. 2009, 86, 215– 223, DOI: 10.1016/j.yexmp.2008.12.004[Crossref], [PubMed], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlslWhtrs%253D&md5=51bbe150de7e5f9db5c27a9717198dffNanoparticle-based targeted drug deliverySingh, Rajesh; Lillard, James W.Experimental and Molecular Pathology (2009), 86 (3), 215-223CODEN: EXMPA6; ISSN:0014-4800. (Elsevier B.V.)A review. Nanotechnol. could be defined as the technol. that has allowed for the control, manipulation, study, and manuf. of structures and devices in the "nanometer" size range. These nano-sized objects, e.g., "nanoparticles", take on novel properties and functions that differ markedly from those seen from items made of identical materials. The small size, customized surface, improved soly., and multi-functionality of nanoparticles will continue to open many doors and create new biomedical applications. Indeed, the novel properties of nanoparticles offer the ability to interact with complex cellular functions in new ways. This rapidly growing field requires cross-disciplinary research and provides opportunities to design and develop multifunctional devices that can target, diagnose, and treat devastating diseases such as cancer. This article presents an overview of nanotechnol. for the biologist and discusses the attributes of the authors' novel XPclad nanoparticle formulation that has shown efficacy in treating solid tumors, single dose vaccination, and oral delivery of therapeutic proteins.133Gupta, A.; Avci, P.; Sadasivam, M.; Chandran, R.; Parizotto, N.; Vecchio, D.; de Melo, W. C. M. A.; Dai, T.; Chiang, L. Y.; Hamblin, M. R. Shining Light on Nanotechnology to Help Repair and Regeneration. Biotechnol. Adv. 2013, 31, 607– 631, DOI: 10.1016/j.biotechadv.2012.08.003[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlWks73P&md5=39dc02860a75e67d45008d22b4e3d4c5Shining light on nanotechnology to help repair and regenerationGupta, Asheesh; Avci, Pinar; Sadasivam, Magesh; Chandran, Rakkiyappan; Parizotto, Nivaldo; Vecchio, Daniela; de Melo, Wanessa C. M. A.; Dai, Tianhong; Chiang, Long Y.; Hamblin, Michael R.Biotechnology Advances (2013), 31 (5), 607-631CODEN: BIADDD; ISSN:0734-9750. (Elsevier)A review. Phototherapy can be used in two completely different but complementary therapeutic applications. While low level laser (or light) therapy (LLLT) uses red or near-IR light alone to reduce inflammation, pain and stimulate tissue repair and regeneration, photodynamic therapy (PDT) uses the combination of light plus non-toxic dyes (called photosensitizers) to produce reactive oxygen species that can kill infectious microorganisms and cancer cells or destroy unwanted tissue (neo-vascularization in the choroid, atherosclerotic plaques in the arteries). The recent development of nanotechnol. applied to medicine (nanomedicine) has opened a new front of advancement in the field of phototherapy and has provided hope for the development of nanoscale drug delivery platforms for effective killing of pathol. cells and to promote repair and regeneration. Despite the well-known beneficial effects of phototherapy and nanomaterials in producing the killing of unwanted cells and promoting repair and regeneration, there are few reports that combine all three elements i.e. phototherapy, nanotechnol. and, tissue repair and regeneration. However, these areas in all possible binary combinations have been addressed by many workers. The present review aims at highlighting the combined multi-model applications of phototherapy, nanotechnol. and, reparative and regeneration medicine and outlines current strategies, future applications and limitations of nanoscale-assisted phototherapy for the management of cancers, microbial infections and other diseases, and to promote tissue repair and regeneration.134Bechet, D.; Couleaud, P.; Frochot, C.; Viriot, M. L.; Guillemin, F.; Barberi-Heyob, M. Nanoparticles as Vehicles for Delivery of Photodynamic Therapy Agents. Trends Biotechnol. 2008, 26, 612– 621, DOI: 10.1016/j.tibtech.2008.07.007[Crossref], [PubMed], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht12lsLjO&md5=ae637c2360d6699269aa6e14b0250c2aNanoparticles as vehicles for delivery of photodynamic therapy agentsBechet, Denise; Couleaud, Pierre; Frochot, Celine; Viriot, Marie-Laure; Guillemin, Francois; Barberi-Heyob, MurielTrends in Biotechnology (2008), 26 (11), 612-621CODEN: TRBIDM; ISSN:0167-7799. (Elsevier B.V.)A review. Photodynamic therapy (PDT) in cancer treatment involves the uptake of a photosensitizer by cancer tissue followed by photoirradn. The use of nanoparticles as carriers of photosensitizers is a very promising approach because these nanomaterials can satisfy all the requirements for an ideal PDT agent. This review describes and compares the different individual types of nanoparticles that are currently in use for PDT applications. Recent advances in the use of nanoparticles, including inorg. oxide-, metallic-, ceramic-, and biodegradable polymer-based nanomaterials as carriers of photosensitizing agents, are highlighted. The authors describe the nanoparticles in terms of stability, photocytotoxic efficiency, biodistribution and therapeutic efficiency. Finally, the authors summarize exciting new results concerning the improvement of the photophys. properties of nanoparticles by biphotonic absorption and upconversion.135Huang, P.; Li, Z.; Lin, J.; Yang, D.; Gao, G.; Xu, C.; Bao, L.; Zhang, C.; Wang, K.; Song, H. Photosensitizer-Conjugated Magnetic Nanoparticles for in Vivo Simultaneous Magnetofluorescent Imaging and Targeting Therapy. Biomaterials 2011, 32, 3447– 3458, DOI: 10.1016/j.biomaterials.2011.01.032[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisVKju74%253D&md5=6afb60b36ad1413ebc2406114e8a22acPhotosensitizer-conjugated magnetic nanoparticles for in vivo simultaneous magnetofluorescent imaging and targeting therapyHuang, Peng; Li, Zhiming; Lin, Jing; Yang, Dapeng; Gao, Guo; Xu, Cheng; Bao, Le; Zhang, Chunlei; Wang, Kan; Song, Hua; Hu, Hengyao; Cui, DaxiangBiomaterials (2011), 32 (13), 3447-3458CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)A major challenge in nanotechnol. and nanomedicine is to integrate tumor targeting, imaging, and selective therapy functions into a small single nanoparticle (< 50 nm). Herein, photosensitizer-conjugated magnetic nanoparticles with ∼20 nm in diam. were strategically designed and prepd. for gastric cancer imaging and therapy. The second generation photosensitizer chlorin e6 (Ce6) was covalently anchored on the surface of magnetic nanoparticles with silane coupling agent. We found that the covalently incorporated Ce6 mols. retained their spectroscopic and functional properties for near-IR (NIR) fluorescence imaging and photodynamic therapy (PDT), and the core magnetic nanoparticles offered the functions of magnetically guided drug delivery and magnetic resonance imaging (MRI). The as-prepd. single particle platform is suitable for simultaneous targeting PDT and in vivo dual-mode NIR fluorescence imaging and MRI of nude mice loaded with gastric cancer or other tumors.136Sun, Y.; Chen, Z. L.; Yang, X. X.; Huang, P.; Zhou, X. P.; Du, X. X. Magnetic Chitosan Nanoparticles as a Drug Delivery System for Targeting Photodynamic Therapy. Nanotechnology 2009, 20, 135102, DOI: 10.1088/0957-4484/20/13/135102[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlvF2qs78%253D&md5=c49cbca7e36253a9a86faec7b0d095a6Magnetic chitosan nanoparticles as a drug delivery system for targeting photodynamic therapySun, Yun; Chen, Zhi-long; Yang, Xiao-xia; Huang, Peng; Zhou, Xin-ping; Du, Xiao-xiaNanotechnology (2009), 20 (13), 135102/1-135102/8CODEN: NNOTER; ISSN:0957-4484. (Institute of Physics Publishing)Photodynamic therapy (PDT) has become an increasingly recognized alternative to cancer treatment in clinic. However, PDT therapy agents, namely photosensitizer (PS), are limited in application as a result of prolonged cutaneous photosensitivity, poor water soly. and inadequate selectivity, which are encountered by numerous chem. therapies. Magnetic chitosan nanoparticles provide excellent biocompatibility, biodegradability, non-toxicity and water soly. without compromising their magnetic targeting. Nevertheless, no previous attempt has been reported to develop an in vivo magnetic drug delivery system with chitosan nanoparticles for magnetic resonance imaging (MRI) monitored targeting photodynamic therapy. In this study, magnetic targeting chitosan nanoparticles (MTCNPs) were prepd. and tailored as a drug delivery system and imaging agents for PS, designated as PHPP. Results showed that PHPP-MTCNPs could be used in MRI monitored targeting PDT with excellent targeting and imaging ability. Non-toxicity and high photodynamic efficacy on SW480 carcinoma cells both in vitro and in vivo were achieved with this method at the level of 0-100 μM. Notably, localization of nanoparticles in skin and hepatic tissue was significantly less than in tumor tissue, therefore photosensitivity and hepatotoxicity can be attenuated.137Wang, S.; Gao, R.; Zhou, F.; Selke, M. Nanomaterials and Singlet Oxygen Photosensitizers: Potential Applications in Photodynamic Therapy. J. Mater. Chem. 2004, 14, 487– 493, DOI: 10.1039/b311429e[Crossref], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtlWms7c%253D&md5=2a4edccceafc7adf2afd1c47995f4cf8Nanomaterials and singlet oxygen photosensitizers: potential applications in photodynamic therapyWang, Shizhong; Gao, Ruomei; Zhou, Feimeng; Selke, MatthiasJournal of Materials Chemistry (2004), 14 (4), 487-493CODEN: JMACEP; ISSN:0959-9428. (Royal Society of Chemistry)In this review, we address a highly interdisciplinary field: the use of nanomaterials as carriers for singlet oxygen photosensitizers and their potential applications in photodynamic therapy. In particular, recent advances in the use of nanoparticles including inorg. oxide-, metallic-, and polymer-based nanocomposites as photosensitizer carriers are highlighted. We review advantages and shortcomings of these diverse approaches as far as their application for photodynamic therapy is concerned. Fullerenes and their derivs. are also included, focusing on recent studies on their structure, properties, and ability to generate singlet oxygen.138Huang, P.; Xu, C.; Lin, J.; Wang, C.; Wang, X.; Zhang, C.; Zhou, X.; Guo, S.; Cui, D. Folic Acid-Conjugated Graphene Oxide Loaded With Photosensitizers for Targeting Photodynamic Therapy. Theranostics 2011, 1, 2240– 250, DOI: 10.7150/thno/v01p0240139Tomao, S. Albumin-Bound Formulation of Paclitaxel (Abraxane Abi-007) in the Treatment of Breast Cancer. Int. J. Nanomed. 2009, 4, 99– 105, DOI: 10.2147/IJN.S3061[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVKjsrrM&md5=5f8b9ded87114b3dc3811851e0d6047eAlbumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancerMiele, Evelina; Spinelli, Gian Paolo; Miele, Ermanno; Tomao, Federica; Tomao, SilverioInternational Journal of Nanomedicine (2009), 4 (), 99-105CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press (NZ) Ltd.)A review. Breast cancer is the most common type of malignancy diagnosed in women. In the metastatic setting this disease is still uncurable. Taxanes represent an important class of antitumor agents which have proven to be fundamental in the treatment of advanced and early-stage breast cancer, but the clin. advances of taxanes have been limited by their highly hydrophobic mol. status. To overcome this poor water soly., lipid-based solvents have been used as a vehicle, and new systemic formulations have been developed, mostly for paclitaxel, which are Cremophor-free and increase the circulation time of the drug. ABI-007 is a novel, albumin-bound, 130-nm particle formulation of paclitaxel, free from any kind of solvent. It has been demonstrated to be superior to an equitoxic dose of std. paclitaxel with a significantly lower incidence of toxicities in a large, international, randomized phase III trial. The availability of new drugs, such as Abraxane, in assocn. with other traditional and non-traditional drugs (new antineoplastic agents and targeted mols.), will give the oncologist many different effective treatment options for patients in this setting.140Malam, Y.; Loizidou, M.; Seifalian, A. M. Liposomes and Nanoparticles: Nanosized Vehicles for Drug Delivery in Cancer. Trends Pharmacol. Sci. 2009, 30, 592– 599, DOI: 10.1016/j.tips.2009.08.004[Crossref], [PubMed], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlCku7zI&md5=6fea99b7e1736f29608d4b02b80a841eLiposomes and nanoparticles: nanosized vehicles for drug delivery in cancerMalam, Yogeshkumar; Loizidou, Marilena; Seifalian, Alexander M.Trends in Pharmacological Sciences (2009), 30 (11), 592-599CODEN: TPHSDY; ISSN:0165-6147. (Elsevier B.V.)A review. Nanoscale drug delivery systems using liposomes and nanoparticles are emerging technologies for the rational delivery of chemotherapeutic drugs in the treatment of cancer. Their use offers improved pharmacokinetic properties, controlled and sustained release of drugs and, more importantly, lower systemic toxicity. The com. availability of liposomal Doxil and albumin-nanoparticle-based Abraxane has focused attention on this innovative and exciting field. Recent advances in liposome technol. offer better treatment of multidrug-resistant cancers and lower cardiotoxicity. Nanoparticles offer increased precision in chemotherapeutic targeting of prostate cancer and new avenues for the treatment of breast cancer. Here we review current knowledge on the two technologies and their potential applications to cancer treatment.141Wilson, B. C.; Olivo, M.; Singh, G. Subcellular Localization of Photofrin and Aminolevulinic Acid and Photodynamic Cross-Resistance in Vitro in Radiation-Induced Fibrosarcoma Cells Sensitive or Resistant to Photofrin-Mediated Photodynamic Therapy. Photochem. Photobiol. 1997, 65, 166– 176, DOI: 10.1111/j.1751-1097.1997.tb01894.x[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlslansg%253D%253D&md5=1d5f1bc5f7554a7aafbb7b56101d15c9Subcellular localization of Photofrin and aminolevulinic acid and photodynamic cross-resistance in vitro in radiation-induced fibrosarcoma cells sensitive or resistant to Photofrin-mediated photodynamic therapyWilson, B. C.; Olivo, M.; Singh, G.Photochemistry and Photobiology (1997), 65 (1), 166-176CODEN: PHCBAP; ISSN:0031-8655. (American Society for Photobiology)The subcellular and, specifically, mitochondrial localization of the photodynamic sensitizers Photofrin and aminolevulinic acid (ALA)-induced protoporphyrin-IX (PpIX) has been investigated in vitro in radiation-induced fibrosarcoma (RIF) tumor cells. Comparisons were made of parental RIF-1 cells and cells (RIF-8A) in which resistance to Photofrin-mediated photodynamic therapy (PDT) has been induced. The effect on the uptake kinetics of Photofrin of coincubation with one of the mitochondria-specific probes 10N-Nonyl acridine orange (NAO) or rhodamine-123 (Rh-123) and vice versa was examd. The subcellular colocalization of Photofrin and PpIX with Rh-123 was detd. by double-label confocal fluorescence microscopy. Clonogenic cell survival after ALA-mediated PDT was detd. in RIF-1 and RIF-8A cells to investigate cross-resistance with Photofrin-mediated PDT. At long (18 h) Photofrin incubation times, stronger colocalization of Photofrin and Rh-123 was seen in RIF-1 than in RIF-8A cells. Differences between RIF-1 and RIF-8A in the competitive mitochondrial binding of NAO or Rh-123 with Photofrin suggest that the inner mitochondrial membrane is a significant Photofrin binding site. The differences in this binding may account for the PDT resistance in RIF-8A cells. With ALA, the peak accumulations of PpIX occurred at 5 h for both cells, and followed a diffuse cytoplasmic distribution compared to mitochondrial localization at 1 h ALA incubation. There was rapid efflux of PpIX from both RIF-1 and RIF-8A. As with Photofrin, ALA-induced PpIX exhibited weaker mitochondrial localization in RIF-8A than in RIF-1 cells. Clonogenic survival demonstrated cross-resistance to incubation in PpIX but not to ALA-induced PpIX, implying differences in mitochondrial localization and/or binding, depending on the source of the PpIX within the cells.142Celli, J. P.; Solban, N.; Liang, A.; Pereira, S. P.; Hasan, T. Verteporfin-Based Photodynamic Therapy Overcomes Gemcitabine Insensitivity in a Panel of Pancreatic Cancer Cell Lines. Lasers Surg. Med. 2011, 43, 565– 574, DOI: 10.1002/lsm.21093[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MbmvFOjsQ%253D%253D&md5=288f096f6bfcc64aefee1de9c1bddad8Verteporfin-based photodynamic therapy overcomes gemcitabine insensitivity in a panel of pancreatic cancer cell linesCelli Jonathan P; Solban Nicolas; Liang Alvin; Pereira Stephen P; Hasan TayyabaLasers in surgery and medicine (2011), 43 (7), 565-74 ISSN:.BACKGROUND AND OBJECTIVE: Pancreatic cancer is notoriously difficult to treat and resistant to virtually all therapeutics including gemcitabine, the standard front line agent for palliative chemotherapy. Early clinical studies point to a potential role for photodynamic therapy (PDT) in the management of this deadly disease. Here we examine PDT with verteporfin for treatment of cells that are nonresponsive to gemcitabine and identify intracellular and extracellular factors that govern sensitivity to each modality. STUDY DESIGN: Using MTS we assess cytotoxicity of verteporfin-PDT in gemcitabine-treated nonresponsive populations from a panel of five pancreatic cancer cell lines representing a range of tumor histopathology and origin. We conduct Western blots for pro-/anti-apoptotic proteins bax and Bcl-XL to identify factors relevant to PDT and gemcitabine sensitivity. To examine the role of extracellular matrix influences we compare response to each modality in traditional cell culture conditions and cells grown on a laminin-rich basement membrane. RESULTS: All cell lines have gemcitabine nonresponsive populations (17-33%) at doses up to 1 mM while moderate total verteporfin PDT doses (1-6 μM J/cm2) produce nearly complete killing. Our data shows that cells that are nonresponsive to sustained gemcitabine incubation are sensitive to verteporfin PDT indicating that the latter is agnostic to gemcitabine sensitivity. Verteporfin-based PDT decreases Bcl-XL and increases the bax/Bcl-XL ratio toward a pro-apoptotic balance. Insensitivity to gemcitabine is increased in cells that are adherent to basement membrane relative to traditional tissue culture conditions. CONCLUSIONS: Collectively these results indicate the ability of verteporfin-based PDT to bypass intracellular and extracellular cues leading to gemcitabine resistance and point to the emerging role of this therapy for treatment of pancreatic cancer.143Mahalingam, S. M.; Ordaz, J. D.; Low, P. S. Targeting of a Photosensitizer to the Mitochondrion Enhances the Potency of Photodynamic Therapy. ACS Omega 2018, 3, 6066– 6074, DOI: 10.1021/acsomega.8b00692[ACS Full Text], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVKmsrzM&md5=2c1106ef23c23ca06e6fe7e3f3bee18aTargeting of a Photosensitizer to the Mitochondrion Enhances the Potency of Photodynamic TherapyMahalingam, Sakkarapalayam M.; Ordaz, Josue D.; Low, Philip S.ACS Omega (2018), 3 (6), 6066-6074CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)Photodynamic therapy (PDT) involves use of a photosensitizer, whose activation with light leads to the prodn. of singlet oxygen (SOS), generation of reactive oxygen species (ROS), and initiation of assocd. cell toxicity. Because a cell's mitochondria constitute sites where oxygen levels are high, ROS can be readily produced, and apoptosis is commonly initiated. Therefore, an ideal PDT agent might be a potent photosensitizer that could naturally accumulate in mitochondria. Although a no. of mitochondria-targeting moieties, including triphenylphosphine, guanidinium, and bisguanidium, have been identified, a quant. comparison of their efficacies in targeting mitochondria has not been performed. In this study, we have prepd. triphenylphosphine, guanidinium, and bisguanidium derivs. of the FDA-approved PDT agent verteporfin (Visudyne, benzoporphyrin deriv.-monoacid ring A: BPD-MA) and compared their abilities to induce the intracellular perturbations common to potent PDT agents. Cellular parameters examd. included subcellular localization of the verteporfin, real-time monitoring of SOS prodn., quantitation of reactive oxygen species (ROS) generation, anal. of mitochondria and chromatin integrity, characterization of cytoskeletal disruption and evaluation of cytochrome C release as a measure of apoptosis. An anal. of these parameters demonstrates that the triphenylphosphine deriv. (0323) has better mitochondria-targeting efficacy, SOS prodn., and mitochondria membrane toxicity than either unmodified verteporfin or its guanidinium derivs. Consistent with this potency, 0323 also induced the most prominent mitochondria swelling, actin depolymn., pyknosis, and cytochrome C release. We conclude that triphenylphosphine has a better mitochondria-targeting moiety than guanidinium or bis-guanidinium and those PDT photosensitizers with improved cytotoxicities can be prepd. by conjugating a mitochondria-targeting moiety to the desired photosensitizer.144Zielonka, J.; Joseph, J.; Sikora, A.; Hardy, M.; Ouari, O.; Vasquez-Vivar, J.; Cheng, G.; Lopez, M.; Kalyanaraman, B. Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications. Chem. Rev. 2017, 117, 10043– 10120, DOI: 10.1021/acs.chemrev.7b00042[ACS Full Text], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVGrs7fJ&md5=53093198d06913e216b0614a8c7ff579Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic ApplicationsZielonka, Jacek; Joseph, Joy; Sikora, Adam; Hardy, Micael; Ouari, Olivier; Vasquez-Vivar, Jeannette; Cheng, Gang; Lopez, Marcos; Kalyanaraman, BalaramanChemical Reviews (Washington, DC, United States) (2017), 117 (15), 10043-10120CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurol. diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small mols. Depending on the approach used, and the potentials of cell and mitochondrial membranes, more than 1000-fold higher mitochondrial concn. can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiol. and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this review, the authors discuss efforts to target small-mol. compds. to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. The authors describe the physicochem. basis for mitochondrial accumulation of lipophilic cations, synthetic chem. strategies to target compds. to mitochondria, mitochondrial probes and sensors, and examples of mitochondrial targeting of bioactive compds. Finally, the authors review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.145Wang, H.; Gao, Z.; Liu, X.; Agarwal, P.; Zhao, S.; Conroy, D. W.; Ji, G.; Yu, J.; Jaroniec, C. P.; Liu, Z.; Lu, X.; Li, X.; He, X. Targeted Production of Reactive Oxygen Species in Mitochondria to Overcome Cancer Drug Resistance. Nat. Commun. 2018, 9, 1– 16, DOI: 10.1038/s41467-018-02915-8[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1KrsrzP&md5=04efe962f0f7b082499e401485f02930Phase and structure engineering of copper tin heterostructures for efficient electrochemical carbon dioxide reductionWang, Pengtang; Qiao, Man; Shao, Qi; Pi, Yecan; Zhu, Xing; Li, Yafei; Huang, XiaoqingNature Communications (2018), 9 (1), 1-10CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)While engineering the phase and structure of electrocatalysts could regulate the performance of many typical electrochem. processes, its importance to the carbon dioxide electroredn. has been largely unexplored. Herein, a series of phase and structure engineered copper-tin dioxide catalysts have been created and thoroughly exploited for the carbon dioxide electroredn. to correlate performance with their unique structures and phases. The copper oxide/hollow tin dioxide heterostructure catalyst exhibits promising performance, which can tune the products from carbon monoxide to formic acid at high faradaic efficiency by simply changing the electrolysis potentials from -0.7 VRHE to -1.0 VRHE. The excellent performance is attributed to the abundant copper/tin dioxide interfaces involved in the copper oxide/hollow tin dioxide heterostructure during the electrochem. process, decreasing the reaction free-energies for the formation of COOH* species. Our work reported herein emphasizes the importance of phase and structure modulating of catalysts for enhancing electrochem. CO2 redn. and beyond.146Zhao, X.; Huang, Y.; Yuan, G.; Zuo, K.; Huang, Y.; Chen, J.; Li, J.; Xue, J. A Novel Tumor and Mitochondria Dual-Targeted Photosensitizer Showing Ultra-Efficient Photodynamic Anticancer Activities. Chem. Commun. 2019, 55, 866– 869, DOI: 10.1039/C8CC09456J[Crossref], [PubMed], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFCksLnL&md5=b2ebbf3e3e6a8c1c921d8006fe912242A novel tumor and mitochondria dual-targeted photosensitizer showing ultra-efficient photodynamic anticancer activitiesZhao, Xuan; Huang, Yuchao; Yuan, Gankun; Zuo, Ke; Huang, Yafan; Chen, Juanjuan; Li, Jinyu; Xue, JinpingChemical Communications (Cambridge, United Kingdom) (2019), 55 (6), 866-869CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)We designed and synthesized a simple, but highly effective photosensitizer (G-Mito-Pc), which can precisely target the mitochondria of epidermal growth factor receptor (EGFR)-overexpressing cancer cells, to achieve dual targeting function at both cell and organelle levels in cancer therapy. We further explored the possible mol. mechanism of the enhanced bioactivity of G-Mito-Pc compared to that of the ref. photosensitizer using mol. dynamics simulations on their interactions with a physiol. relevant mitochondrial membrane model.147Sibrian-Vazquez, M.; Nesterova, I. V.; Jensen, T. J.; Vicente, M. G. H. Mitochondria Targeting by Guanidine- and Biguanidine-Porphyrin Photosensitizers. Bioconjugate Chem. 2008, 19, 705– 713, DOI: 10.1021/bc700393u[ACS Full Text], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhvVGgu7g%253D&md5=773afe6be2634fd0174f9593a56923c0Mitochondria Targeting by Guanidine- and Biguanidine-Porphyrin PhotosensitizersSibrian-Vazquez, Martha; Nesterova, Irina V.; Jensen, Timothy J.; Vicente, M. Graca H.Bioconjugate Chemistry (2008), 19 (3), 705-713CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)We report the syntheses of three new amphiphilic porphyrin derivs., contg. a guanidine, a biguanidine, or an MLS peptide, that were designed to target the cell mitochondria. The guanidine- and biguanidine-porphyrins are poorly sol. in water, forming J-type aggregates in aq. solns. On the other hand, the porphyrin-MLS peptide conjugate bearing a low mol. wt. PEG spacer is highly water-sol. and does not aggregate in aq. media. The fluorescence quantum yields detd. for all porphyrins were higher at low pH (<6) and the porphyrin-peptide conjugate had the highest quantum yields in aq. media. All porphyrins showed low dark toxicity toward human carcinoma HEp2 cells, and the guanidine-porphyrin was the most phototoxic (IC50 = 4.8 μM at 1 J cm-2), followed by the biguanidine-porphyrin and the porphyrin-MLS (IC50 = 8.2 μM and 9.8 μM at 1 J cm-2, resp.). The porphyrin-MLS peptide conjugate accumulated the most within cells of all porphyrins at all times investigated and the biguanidine-porphyrin accumulated the least. Both the guanidine- and biguanidine-porphyrins localized within cell mitochondria and, in addn., were found in the lysosomes and the ER (in the case of the guanidine-porphyrin). In contrast, the porphyrin-MLS peptide conjugate localized mainly within the cell lysosomes.148Canal, F.; Vicent, M. J.; Pasut, G.; Schiavon, O. Relevance of Folic Acid/Polymer Ratio in Targeted PEG-Epirubicin Conjugates. J. Controlled Release 2010, 146, 388– 399, DOI: 10.1016/j.jconrel.2010.05.027[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFWgt7vF&md5=7ed2bb3bc3bb6a29d3bfabcac7bc8422Relevance of folic acid/polymer ratio in targeted PEG-epirubicin conjugatesCanal, Fabiana; Vicent, Maria J.; Pasut, Gianfranco; Schiavon, OddoneJournal of Controlled Release (2010), 146 (3), 388-399CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A series of PEG-epirubicin conjugates with different folic acid contents per polymer chain was synthesized in order to study the influence of polymer/targeting moiety ratio on selective cytotoxicity, cellular uptake and intracellular localization. Analogous carboxyl-terminated conjugates without folic acid were studied as control. The heterobifunctional HO-PEG-COOH was used as polymeric carrier, allowing the synthesis of conjugates with a good control over the chem. structure and the drug/polymer and polymer/targeting residue ratios. A dendron structure was synthesized at one end of the PEG chain with the aim to increase the no. of folic acid mols. L-2-aminoadipic acid was used as branching unit. The conjugates showed high stability under several physiol. conditions. Biol. evaluation was carried out in A549, HeLa and KB-3-1 human cell lines, as these cells have different levels of folate receptor (FR) expression. In particular A549 cells are FR neg. (FR-), HeLa cells are FR pos. (FR+) and KB-3-1 cells over-express FR (FR++). It was clearly shown that the biol. activity of the conjugates was influenced by the presence and the no. of folic acid mols. per polymer chain and by the level of FR expression on cell surface. Conjugates conformation in soln. was also studied, as differences in size might well affect cell internalization. In the cell viability assay, conjugates without folic acid were unexpectedly more cytotoxic than the targeted conjugates, but their IC50 values were similar in the three cell lines. Differently, the anti-proliferative activity of targeted derivs. markedly increased going from FR(-) to FR(++) cells. FACS and confocal microscopy studies showed greater cellular internalization with the targeted conjugates than with their non-targeted analogs; more importantly, this relationship is clearly dependent on folic acid content in the conjugates and FR expression level in the cell line used.149Farokhzad, O. C.; Langer, R. Impact of Nanotechnology on Drug Delivery. ACS Nano 2009, 3, 16– 20, DOI: 10.1021/nn900002m[ACS Full Text], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnvFGisQ%253D%253D&md5=092946aed00c4a9f740df6505b2e805cImpact of Nanotechnology on Drug DeliveryFarokhzad, Omid C.; Langer, RobertACS Nano (2009), 3 (1), 16-20CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)A review. Nanotechnol. is the engineering and manufg. of materials at the at. and mol. scale. In its strictest definition from the National Nanotechnol. Initiative, nanotechnol. refers to structures roughly in the 1-100 nm size regime in at least one dimension. Despite this size restriction, nanotechnol. commonly refers to structures that are up to several hundred nanometers in size and that are developed by top-down or bottom-up engineering of individual components. Herein, we focus on the application of nanotechnol. to drug delivery and highlight several areas of opportunity where current and emerging nanotechnologies could enable entirely novel classes of therapeutics.150Lin, L.; Xiong, L.; Wen, Y.; Lei, S.; Deng, X.; Liu, Z.; Chen, W.; Miao, X. Active Targeting of Nano-Photosensitizer Delivery Systems for Photodynamic Therapy of Cancer Stem Cells. J. Biomed. Nanotechnol. 2015, 11, 531– 554, DOI: 10.1166/jbn.2015.2090[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlt1Ggtrk%253D&md5=69cbcdd4b863a3e3a4c53a60835d3594Active targeting of nano-photosensitizer delivery systems for photodynamic therapy of cancer stem cellsLin, Liangwu; Xiong, Li; Wen, Yu; Lei, Sanlin; Deng, Xiaofeng; Liu, Zhipeng; Chen, Wei; Miao, XiongyingJournal of Biomedical Nanotechnology (2015), 11 (4), 531-554CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)A review. Cancer stem cells are believed to be the basis for tumor initiation, development, metastasis and recurrence; are resistant to most traditional therapies (e.g., chemotherapy and radiotherapy); and have the ability to self-renew, proliferate and differentiate. Photodynamic therapy may be a promising novel treatment for drug-resistant cancer stem cells because of the selectivity of the photosensitizer. One of the most important issues to overcome in photodynamic therapy is the photosensitizer-targeted delivery to tumor cells, esp. cancer stem cells. Nano-photosensitizers comprising mol. photosensitizers and water-dispersible nanocarriers with or without moieties possessing the ability for specific binding to cancer cells or cancer stem cells are a promising strategy for active targeted photosensitizer delivery and photodynamic therapy-targeted therapy of tumors. In this review, we highlight current and future prospects for potential strategies based on nanoscience and nanotechnol. for nano-photosensitizer-targeted delivery in the photodynamic therapy treatment of cancer cells, esp. cancer stem cells.151Chen, L.; Miao, W.; Tang, X.; Zhang, H.; Wang, S.; Luo, F.; Yan, J. Inhibitory Effect of Neuropilin-1 Monoclonal Antibody (NRP-1 MAB) on Glioma Tumor in Mice. J. Biomed. Nanotechnol. 2013, 9, 551– 558, DOI: 10.1166/jbn.2013.1623[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltlGqsrk%253D&md5=3787730e120f9b3fbc8c6a997ae20382Inhibitory effect of neuropilin-1 monoclonal antibody (NRP-1 MAb) on glioma tumor in miceChen, Lukui; Miao, Wei; Tang, Xiaoyong; Zhang, Haipeng; Wang, Shengyu; Luo, Fanghong; Yan, JianghuaJournal of Biomedical Nanotechnology (2013), 9 (4), 551-558CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)This article reports the effect of Neuropilin-1 monoclonal antibody (NRP-1 MAb) on glioma cell lines in vitro and the effect on nude mice bearing glioma tumor (U87) in vivo. MTT, the scratch test and transwell test were used to evaluate the inhibitory effect of NRP-1 MAb on glioma cell lines. The tissue distribution and tumor targeting capability of NRP-1 MAb in U87 Xenografts nude mice was detd. in Optical Imaging. Anti-glioma expt. was carried out by NRP-1 MAb on U87 Xenografts nude mice. NRP-1 MAb was showed to inhibit the proliferation, migration and invasion of glioma cells. NRP-1 MAb can specifically target the tumor in U87 Xenografts nude mice and reduce the proliferation activity of the tumor. The results of this study indicate that NRP-1 MAb can inhibit the proliferation, migration and metastasis of glioma cell lines and can target the glioma tumor to reduce tumor growth. Therefore, NRP-1 MAb may be an effective agent for glioma-targeted therapy.152Zhang, Z.; Sun, Q.; Zhong, J.; Yang, Q.; Li, H.; Cheng, D.; Liang, B.; Shuai, X. Magnetic Resonance Imaging-Visible and PH-Sensitive Polymeric Micelles for Tumor Targeted Drug Delivery. J. Biomed. Nanotechnol. 2014, 10, 216– 226, DOI: 10.1166/jbn.2014.1729[Crossref], [PubMed], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkvV2iu7w%253D&md5=2539e7dd35175465924a6fd90a571127Magnetic resonance imaging-visible and pH-sensitive polymeric micelles for tumor targeted drug deliveryZhang, Zuoquan; Sun, Qiquan; Zhong, Jinglian; Yang, Qihua; Li, Hao; Cheng, Du; Liang, Biling; Shuai, XintaoJournal of Biomedical Nanotechnology (2014), 10 (2), 216-226CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)Folate-functionalized copolymers of poly(ethylene glycol) and 2-(diisopropylamino) ethylamine grafted poly(L-aspartic acid) are synthesized. The copolymers can self-assemble into nanoscaled micelles encapsulated with hydrophobic model drug Fluorescein Diacetate (FDA) and MRI diagnostic agents superparamagnetic iron oxide nanoparticles (SPIONs) in aq. soln. of a neutral pH resembling physiol. environment, whereas disassemble in acidic endosomal/lysosomal compartments of tumor cells to achieve rapid drug release. In vitro drug release study showed that FDA release from the pH-sensitive micelles was much faster at pH 5.0 than at pH 7.4. Clustering of SPIONs inside the hydrophobic core of the micelles resulted in a high spin-spin (T2) relaxivity for a super MRI sensitivity. Cell culture studies showed that the FDA-SPION-loaded micelles were effectively internalized by human hepatic Bel-7402 cancer cells following a folate receptor-mediated targeting mechanism, and then FDA was rapidly release from micelles inside lysosomal compartments. Micelles encapsulating paclitaxel (PTX) studies showed it can induce more effective cell toxicity. This study demonstrated the great potential of the pH-sensitive micelles as an effective multifunctional nanomedician platform for cancer therapy due to their active tumor targeting, pH-triggered drug release and ultrasensitive MRI responsiveness.153Kim, K. S.; Kim, J.; Kim, D. H.; Hwang, H. S.; Na, K. Multifunctional Trastuzumab-Chlorin E6 Conjugate for the Treatment of HER2-Positive Human Breast Cancer. Biomater. Sci. 2018, 6, 1217– 1226, DOI: 10.1039/C7BM01084B[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXkt1Kgurk%253D&md5=133b9940dbb9a61a3fded1e27ca9ad66Multifunctional trastuzumab-chlorin e6 conjugate for the treatment of HER2-positive human breast cancerKim, Kyoung Sub; Kim, Jiyoung; Kim, Da Hye; Hwang, Hee Sook; Na, KunBiomaterials Science (2018), 6 (5), 1217-1226CODEN: BSICCH; ISSN:2047-4849. (Royal Society of Chemistry)Effective penetration and targeted delivery of anticancer drugs into tumor tissues are limiting factors for achieving enhanced therapeutic efficacy. In order to overcome the disadvantages of antibody therapy (limited penetration efficacy into tumor tissues) and photodynamic therapy (low targeting efficiency) on the treatment of HER2-pos. human breast cancer simultaneously, an antibody and photosensitizer combined Trastuzumab-chlorin e6 conjugate (TMPC) was synthesized. TMPC exhibits high singlet oxygen generation under laser irradn. In vitro data show that TMPC has specific HER2 selective interactions, and ROS generation ability upon laser irradn. induces significant cell death in HER2-pos. breast cancer cells. The enhanced tissue penetration ability and tissue access of TMPC resulting from local tissue destruction by ROS generated from Ce6 is also demonstrated in breast cancer tissue blocks. The enhanced ability of TMPC is supported by in vivo fluorescence images of SK-BR-3 (HER2-pos. cancer cells) tumor-bearing mice. The in vivo test demonstrates approx. 6-fold enhanced accumulation of TMPC in xenograft tumors with a longer retention time compared to that of the PEG-Ce6 conjugate at 24 h. Thus, trastuzumab and photosensitizer conjugation brings synergistic effects for HER2 selective targeting, where TMPC enhanced tumor tissue penetration improves tumor tissue access and responsiveness of trastuzumab in HER2 overexpressing breast cancer.154Mitri, Z.; Constantine, T.; O’Regan, R. The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy. Chemother. Res. Pract. 2012, 2012, 1– 7, DOI: 10.1155/2012/743193155Kim, J.; Jo, Y. um; Na, K. Photodynamic Therapy with Smart Nanomedicine. Arch. Pharmacal Res. 2020, 43, 22– 31, DOI: 10.1007/s12272-020-01214-5[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisleksbo%253D&md5=9f2dc55f9012722a782c303612f030f4Photodynamic therapy with smart nanomedicineKim, Jiyoung; Jo, Young-um; Na, KunArchives of Pharmacal Research (2020), 43 (1), 22-31CODEN: APHRDQ; ISSN:0253-6269. (Pharmaceutical Society of Korea)Abstr.: For several decades, clin. demands for utilization of photodynamic therapy (PDT) have been increasing. Notably, PDT was mainly applied for cancer therapy, and most photosensitizers (PSs) were developed to treat cancer. The advantages of PDT, such as minimal invasiveness and local treatment by topical light irradn., have made it possible to widen the range of target diseases. Thus, PDT has been clin. used for treatment of various diseases (e.g., cancer, acne, and age-related macular degeneration). However, PS, which is the main component of PDT, exhibits several shortcomings such as low soly., low bioavailability, and lack of lesion selectivity for use as a therapeutic agent. Therefore, many research projects have been performed to develop smart PS. To increase therapeutic efficacy and to decrease adverse effects in normal tissue at the same time, PS incorporation within nanoscaled delivery systems is evolving. This review provides a comprehensive explanation of PDT in smart nanomedicine, which is academically and clin. utilized in the treatment of various diseases.156Kessel, D. The Role of Low-Density Lipoprotein in the Biodistribution of Photosensitizing Agents. J. Photochem. Photobiol., B 1992, 14, 261– 262, DOI: 10.1016/1011-1344(92)85103-2[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3s%252FlvVWgtA%253D%253D&md5=c0f0f7b227d822c811d874f96aa6fba8The role of low-density lipoprotein in the biodistribution of photosensitizing agentsKessel DJournal of photochemistry and photobiology. B, Biology (1992), 14 (3), 261-2 ISSN:1011-1344.There is no expanded citation for this reference.157Sibani, S. A.; McCarron, P. A.; Woolfson, A. D.; Donnelly, R. F. Photosensitiser Delivery for Photodynamic Therapy. Part 2: Systemic Carrier Platforms. Expert Opin. Drug Delivery 2008, 5, 1241– 1254, DOI: 10.1517/17425240802444673[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlaisrfN&md5=d33451d4188ccdeb2101bf2083ce6642Photosensitiser delivery for photodynamic therapy. Part 2: systemic carrier platformsSibani, Stephane A.; McCarron, Paul A.; Woolfson, A. David; Donnelly, Ryan F.Expert Opinion on Drug Delivery (2008), 5 (11), 1241-1254CODEN: EODDAW; ISSN:1742-5247. (Informa Healthcare)A review. Background: The treatment of solid tumors and angiogenic ocular diseases by photodynamic therapy (PDT) requires the injection of a photosensitizer (PS) to destroy target cells through a combination of visible light irradn. and mol. oxygen. There is currently great interest in the development of efficient and specific carrier delivery platforms for systemic PDT. Objective: This article aims to review recent developments in systemic carrier delivery platforms for PDT, with an emphasis on target specificity. Methods: Recent publications, spanning the last five years, concerning delivery carrier platforms for systemic PDT were reviewed, including PS conjugates, dendrimers, micelles, liposomes and nanoparticles. Results/conclusion: PS conjugates and supramol. delivery platforms can improve PDT selectivity by exploiting cellular and physiol. specificities of the targeted tissue. Overexpression of receptors in cancer and angiogenic endothelial cells allows their targeting by affinity-based moieties for the selective uptake of PS conjugates and encapsulating delivery carriers, while the abnormal tumor neovascularisation induces a specific accumulation of heavy weighted PS carriers by enhanced permeability and retention (EPR) effect. In addn., polymeric prodrug delivery platforms triggered by the acidic nature of the tumor environment or the expression of proteases can be designed. Promising results obtained with recent systemic carrier platforms will, in due course, be translated into the clinic for highly efficient and selective PDT protocols.158Ke, M.-R.; Yeung, S.-L.; Ng, D. K. P.; Fong, W.-P.; Lo, P.-C. Preparation and In Vitro Photodynamic Activities of Folate-Conjugated Distyryl Boron Dipyrromethene Based Photosensitizers. J. Med. Chem. 2013, 56, 8475– 8483, DOI: 10.1021/jm4009168[ACS Full Text], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFKlu7jO&md5=6756371bb8d6718a4f46afe42cdab588Preparation and in Vitro Photodynamic Activities of Folate-Conjugated Distyryl Boron Dipyrromethene Based PhotosensitizersKe, Mei-Rong; Yeung, Sin-Lui; Ng, Dennis K. P.; Fong, Wing-Ping; Lo, Pui-ChiJournal of Medicinal Chemistry (2013), 56 (21), 8475-8483CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Two folate-conjugated diiododistyryl boron dipyrromethenes have been prepd. and characterized with various spectroscopic methods. These conjugates exhibit higher photocytotoxicity toward the KB human nasopharyngeal carcinoma cells, which have high expression of folate receptors when compared with the MCF-7 human breast adenocarcinoma cells, which have low expression of folate receptors. The difference in photocytotoxicity for these two cell lines is particularly large for the conjugate with a shorter oligoethylene glycol linker (compd. 11a) as a result of its higher cellular uptake and slightly lower aggregation tendency. Its IC50 value toward KB cells (0.06 μM) is 43-fold lower than that for MCF-7 cells, while the difference is only 6-fold for the analog with a longer linker (compd. 11b). The length of the spacer also affects their subcellular localization. While compd. 11a shows high affinity toward the endoplasmic reticulum of KB cells, conjugate 11b is mainly localized in the lysosomes.159Cheung, A.; Bax, H. J.; Josephs, D. H.; Ilieva, K. M.; Pellizzari, G.; Opzoomer, J.; Bloomfield, J.; Fittall, M.; Grigoriadis, A.; Figini, M.; Canevari, S.; Spicer, J. F.; Tutt, A. N.; Karagiannis, S. N. Targeting Folate Receptor Alpha for Cancer Treatment. Oncotarget 2016, 7, 52553– 52574, DOI: 10.18632/oncotarget.9651[Crossref], [PubMed], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s%252FlsVantA%253D%253D&md5=cac31bd8f8f082eca3ce9041770e4a23Targeting folate receptor alpha for cancer treatmentCheung Anthony; Bax Heather J; Josephs Debra H; Ilieva Kristina M; Pellizzari Giulia; Opzoomer James; Bloomfield Jacinta; Fittall Matthew; Karagiannis Sophia N; Cheung Anthony; Ilieva Kristina M; Fittall Matthew; Grigoriadis Anita; Tutt Andrew N; Karagiannis Sophia N; Bax Heather J; Josephs Debra H; Spicer James F; Figini Mariangela; Canevari SilvanaOncotarget (2016), 7 (32), 52553-52574 ISSN:.Promising targeted treatments and immunotherapy strategies in oncology and advancements in our understanding of molecular pathways that underpin cancer development have reignited interest in the tumor-associated antigen Folate Receptor alpha (FRα). FRα is a glycosylphosphatidylinositol (GPI)-anchored membrane protein. Its overexpression in tumors such as ovarian, breast and lung cancers, low and restricted distribution in normal tissues, alongside emerging insights into tumor-promoting functions and association of expression with patient prognosis, together render FRα an attractive therapeutic target. In this review, we summarize the role of FRα in cancer development, we consider FRα as a potential diagnostic and prognostic tool, and we discuss different targeted treatment approaches with a specific focus on monoclonal antibodies. Renewed attention to FRα may point to novel individualized treatment approaches to improve the clinical management of patient groups that do not adequately benefit from current conventional therapies.160Savellano, M. D.; Hasan, T. Photochemical Targeting of Epidermal Growth Factor Receptor: A Mechanistic Study. Clin. Cancer Res. 2005, 11, 1658– 1668, DOI: 10.1158/1078-0432.CCR-04-1902[Crossref], [PubMed], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhvVSrt7o%253D&md5=de8810d77e74a48274758152edcd5c68Photochemical Targeting of Epidermal Growth Factor Receptor: A Mechanistic StudySavellano, Mark D.; Hasan, TayyabaClinical Cancer Research (2005), 11 (4), 1658-1668CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)PURPOSE: Photoimmunotherapy may allow target-specific photodynamic destruction of malignancies and may also potentiate anticancer antibody therapies. However, clin. use of either of the two modalities is limited for different reasons. Antibody therapies suffer from being primarily cytostatic and the need for prolonged administration with consequent side effects. In the case of photoimmunotherapy, a major impediment has been the absence of well-characterized photosensitizer immunoconjugates (PIC). In this investigation, we suggest a strategy to overcome these limitations and present the successful targeting of epidermal growth factor receptor (EGFR) using a well-characterized PIC. Exptl. Design: The PIC consisted of the EGFR-recognizing chimeric monoclonal antibody, C225, conjugated with a two-branched polyethylene glycol and benzoporphyrin deriv. (BPD, Verteporfin). Mechanistic studies included photophysics, phototoxicity, cellular uptake, and catabolism expts. to yield dosimetric parameters. Target cells included two EGFR-overexpressing human cancer cell lines, OVCAR-5 and A-431. Nontarget cells included an EGFR-neg. fibroblast cell line, 3T3-NR6, and a monocyte-macrophage cell line, J774. RESULTS: BPD-C225 PICs targeted and photodynamically killed EGFR-overexpressing cells, whereas free BPD exhibited no specificity. On a per mol basis, PICs were less phototoxic than free BPD, but PICs were very selective for target cells, whereas free BPD was not. Phototoxicity of the PICs increased at prolonged incubations. Photodynamic dose calcns. indicated that PIC photophysics, photochem., catabolism, and subcellular localization were important determinants of PIC phototoxic potency. CONCLUSIONS: This study shows the efficacy of EGFR targeting with PIC constructs and suggests approaches to improve PIC designs and targeting strategies for in vivo photoimmunotherapy. The approach offers the possibility of dual effects via antibody-mediated cytostasis and photoimmunotherapy-based cytotoxicity.161Choi, Y.; McCarthy, J. R.; Weissleder, R.; Tung, C. H. Conjugation of a Photosensitizer to an Oligoarginine-Based Cell-Penetrating Peptide Increases the Efficacy of Photodynamic Therapy. ChemMedChem 2006, 1, 458– 463, DOI: 10.1002/cmdc.200500036[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xjslehuro%253D&md5=d2715b0409f9c17718ab31a0bd6b44f6Conjugation of a photosensitizer to an oligoarginine-based cell-penetrating peptide increases the efficacy of photodynamic therapyChoi, Yongdoo; McCarthy, Jason R.; Weissleder, Ralph; Tung, Ching-HsuanChemMedChem (2006), 1 (4), 458-463CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)To improve the efficiency of intracellular delivery of photosensitizers and the efficacy of photodynamic therapy, a membrane-penetrating arginine oligopeptide (R7) was conjugated to 5-[4-carboxyphenyl]-10,15,20-triphenyl-2,3-dihydroxychlorin (TPC). The resulting conjugate (R7-TPC) enhanced intracellular TPC uptake, which increased proportionally with the incubation time of the conjugate. The water soly. of the highly hydrophobic TPC photosensitizer was also improved after conjugation. Increased phototoxicity of R7-TPC was obsd. after an incubation time of only 30 min. Tumor cells mainly underwent apoptosis at lower concns. of the photosensitizer-polyarginine conjugate, whereas necrotic cell damage became prevalent at higher concns.162Minchinton, A. I.; Tannock, I. F. Drug Penetration in Solid Tumours. Nat. Rev. Cancer 2006, 6, 583– 592, DOI: 10.1038/nrc1893[Crossref], [PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XntFGlu7w%253D&md5=89afe4c91bdf6080f16dc13e4dd1e140Drug penetration in solid tumoursMinchinton, Andrew I.; Tannock, Ian F.Nature Reviews Cancer (2006), 6 (8), 583-592CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. To be most effective anticancer drugs must penetrate tissue efficiently, reaching all the cancer cells that comprise the target population in a concn. sufficient to exert a therapeutic effect. Most research into the resistance of cancers to chemotherapy has concd. on mol. mechanisms of resistance, whereas the role of limited drug distribution within tumors has been neglected. We summarize the evidence that indicates that the distribution of many anticancer drugs in tumor tissue is incomplete, and we suggest strategies that might be used either to improve drug penetration through tumor tissue or to select compds. based on their abilities to penetrate tissue, thereby increasing the therapeutic index.163Greish, K. Enhanced Permeability and Retention (Epr) Effect for Anticancer Nanomedicine Drug Targeting. Methods Mol. Biol. 2010, 624, 25– 37, DOI: 10.1007/978-1-60761-609-2_3[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvVymu78%253D&md5=22dd10c42cbd982a7c2fba9ef399ce53Enhanced permeability and retention (EPR) effect for anticancer nanomedicine drug targetingGreish, KhaledMethods in Molecular Biology (Totowa, NJ, United States) (2010), 624 (Cancer Nanotechnology), 25-37CODEN: MMBIED; ISSN:1064-3745. (Humana Press Inc.)A review. Effective cancer therapy remains one of the most challenging tasks to the scientific community, with little advancement on overall cancer survival landscape during the last two decades. A major limitation inherent to most conventional anticancer chemotherapeutic agents is their lack of tumor selectivity. One way to achieve selective drug targeting to solid tumors is to exploit abnormalities of tumor vasculature, namely hypervascularization, aberrant vascular architecture, extensive prodn. of vascular permeability factors stimulating extravasation within tumor tissues, and lack of lymphatic drainage. Due to their large size, nano-sized macromol. anticancer drugs administered i.v. escape renal clearance. Being unable to penetrate through tight endothelial junctions of normal blood vessels, their concn. builds up in the plasma rendering them long plasma half-life. More importantly, they can selectively extravasate in tumor tissues due to its abnormal vascular nature. Overtime the tumor concn. will build up reaching several folds higher than that of the plasma due to lack of efficient lymphatic drainage in solid tumor, an ideal application for EPR-based selective anticancer nanotherapy. Indeed, this selective high local concn. of nano-sized anticancer drugs in tumor tissues has proven superior in therapeutic effect with minimal side effects in both preclin. and clin. settings.164McNeil, S. E. Nanotechnology for the Biologist. J. Leukocyte Biol. 2005, 78, 585– 594, DOI: 10.1189/jlb.0205074[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVSksbzI&md5=e80230b6a0859315787c2e43dbd74797Nanotechnology for the biologistMcNeil, Scott E.Journal of Leukocyte Biology (2005), 78 (3), 585-594CODEN: JLBIE7; ISSN:0741-5400. (Federation of American Societies for Experimental Biology)A review. Nanotechnol. refers to research and technol. development at the at., mol., and macromol. scale, leading to the controlled manipulation and study of structures and devices with length scales in the 1-100-nm range. Objects at this scale, such as "nanoparticles," take on novel properties and functions that differ markedly from those seen on the bulk scale. The small size, surface tailorability, improved soly., and multifunctionality of nanoparticles open many new research avenues for biologists. The novel properties of nanomaterials offer the ability to interact with complex biol. functions in new ways, operating at the very scale of biomols. This rapidly growing field allows cross-disciplinary researchers the opportunity to design and develop multifunctional nanoparticles that can target, diagnose, and treat diseases such as cancer. Here, the author presents an overview of nanotechnol. for the biologist and discusses "nanotech" strategies and constructs that have already demonstrated in vitro and in vivo efficacy.165Tanaka, M.; Kataoka, H.; Yano, S.; Ohi, H.; Moriwaki, K.; Akashi, H.; Taguchi, T.; Hayashi, N.; Hamano, S.; Mori, Y.; Kubota, E.; Tanida, S.; Joh, T. Antitumor Effects in Gastrointestinal Stromal Tumors Using Photodynamic Therapy With a Novel Glucose-Conjugated Chlorin. Mol. Cancer Ther. 2014, 13, 767– 775, DOI: 10.1158/1535-7163.MCT-13-0393[Crossref], [PubMed], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXls1Gjtbs%253D&md5=c266bcac5b6a7a49d046554f0bcd8728Antitumor Effects in Gastrointestinal Stromal Tumors Using Photodynamic Therapy with a Novel Glucose-Conjugated ChlorinTanaka, Mamoru; Kataoka, Hiromi; Yano, Shigenobu; Ohi, Hiromi; Moriwaki, Kazuhiro; Akashi, Haruo; Taguchi, Takahiro; Hayashi, Noriyuki; Hamano, Shingo; Mori, Yoshinori; Kubota, Eiji; Tanida, Satoshi; Joh, TakashiMolecular Cancer Therapeutics (2014), 13 (4), 767-775CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Except for surgical resection, no effective treatment strategies have been established. Photodynamic therapy (PDT) consists of i.v. administration of a photosensitizer, activated by a specific wavelength of light, which produces reactive oxygen species that directly kill tumor cells. We analyzed the efficacy of PDT using a newly developed photosensitizer, 5,10,15,20-tetrakis [4-[β-d-glucopyranosylthio-2,3,5,6-tetrafluorophenyl]-2,3,[methano[N-methyl] iminomethano]chlorin (H2TFPC-SGlc), for the GIST treatment. Various photosensitizers were administered in vitro to GIST (GIST-T1) and fibroblast (WI-38) cells, followed by irradn., after which cell death was compared. We addnl. established xenograft mouse models with GIST-T1 tumors and examd. the accumulation and antitumor effects of these photosensitizers in vivo. In vitro, the expression of the glucose transporters GLUT1, GLUT3, and GLUT4, the cellular uptake of H2TFPC-SGlc, and apoptosis mediated by PDT with H2TFPC-SGlc were significantly higher in GIST-T1 than in WI-38 cells. In vivo, H2TFPC-SGlc accumulation was higher in xenograft tumors of GIST-T1 cells than in the adjacent normal tissue, and tumor growth was significantly suppressed following PDT. PDT with novel H2TFPC-SGlc is potentially useful for clin. applications about the treatment of GIST. Mol Cancer Ther; 13(4); 767-75. ©2014 AACR.166Jain, R. K. Delivery of Molecular and Cellular Medicine to Solid Tumors. Adv. Drug Delivery Rev. 2001, 46, 149– 168, DOI: 10.1016/S0169-409X(00)00131-9[Crossref], [PubMed], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXitVOhsLw%253D&md5=e8e5acd4b3f7a7c4fe647179537681efDelivery of molecular and cellular medicine to solid tumorsJain, R. K.Advanced Drug Delivery Reviews (2001), 46 (1-3), 149-168CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science Ireland Ltd.)A review, with 151 refs. To reach cancer cells in a tumor, a blood-borne therapeutic mol. or cell must make its way into the blood vessels of the tumor and across the vessel wall into the interstitium, and finally migrate through the interstitium. Unfortunately, tumors often develop in ways that hinder each of these steps. Our research goals are to analyze each of these steps exptl. and theor., and then integrate the resulting information in a unified theor. framework. This paradigm of anal. and synthesis has allowed us to obtain a better understanding of physiol. barriers in solid tumors, and to develop novel strategies to exploit and/or to overcome these barriers for improved cancer detection and treatment.167Decuzzi, P.; Causa, F.; Ferrari, M.; Netti, P. A. The Effective Dispersion of Nanovectors Within the Tumor Microvasculature. Ann. Biomed. Eng. 2006, 34, 633– 641, DOI: 10.1007/s10439-005-9072-6[Crossref], [PubMed], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD283hsVGitw%253D%253D&md5=7cd4bfb5606b3985890de37ee49613abThe effective dispersion of nanovectors within the tumor microvasculatureDecuzzi P; Causa F; Ferrari M; Netti P AAnnals of biomedical engineering (2006), 34 (4), 633-41 ISSN:0090-6964.The effective longitudinal diffusion of nanovectors along non-permeable and permeable capillaries has been studied considering the contribution of molecular and convective diffusion based on the Taylor's theory of shear dispersion. The problem is of importance in the transport of nanovectors used for the intravascular delivery of drugs and contrast agents. It has been shown that for a given capillary size and hemodynamic conditions a critical radius acr exists for which the effective longitudinal diffusion along the capillary has a minimum: Nanovectors with a < acr diffuse mainly by Brownian diffusion whereas nanovectors with a < acr diffuse mainly by convection and the effective diffusion coefficient grows with a. In permeable conduits, the effective diffusion reduces significantly compared to normal non-leaky vessels and it has been derived that acr grows almost linearly with the hydraulic permeability Lp of blood vessels. It has been shown that the blood conduits with the largest effective longitudinal diffusivity could be preferentially targeted by the circulating vectors. Based on these findings, the following strategies are proposed to increase the number of nanovectors targeting the tumor vessels: (i) The use of nanovectors with a critical radius for normal vessels, (ii) the injecting of bolus of nanovectors with different radii, and (iii) the normalization of the tumor vasculature. Finally, it has been emphasized that the size of the vector should be selected depending on the body district where the tumoral mass is developing and on the type, malignancy, and state of the tumor.168Decuzzi, P.; Lee, S.; Bhushan, B.; Ferrari, M. A Theoretical Model for the Margination of Particles Within Blood Vessels. Ann. Biomed. Eng. 2005, 33, 179– 190, DOI: 10.1007/s10439-005-8976-5[Crossref], [PubMed], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M7jvFentw%253D%253D&md5=e7c7371efa9b47fe5532df67119cb308A theoretical model for the margination of particles within blood vesselsDecuzzi P; Lee S; Bhushan B; Ferrari MAnnals of biomedical engineering (2005), 33 (2), 179-90 ISSN:0090-6964.The margination of a particle circulating in the blood stream has been analyzed. The contribution of buoyancy, hemodynamic forces, van der Waals, electrostatic and steric interactions between the circulating particle and the endothelium lining the vasculature has been considered. For practical applications, the contribution of buoyancy, hemodynamic forces and van der Waals interactions should be only taken into account, whilst the effect of electrostatic and steric repulsion becomes important only at very short distances from the endothelium (1-10 nm). The margination speed and the time for margination t(s) have been estimated as a function of the density of the particle relative to blood delta rho, the Hamaker constant A and radius R of the particle. A critical radius Rc exists for which the margination time t(s) has a maximum, which is influenced by both delta rho and A: the critical radius decreases as the relative density increases and the Hamaker constant decreases. Therefore, particles used for drug delivery should have a radius smaller than the critical value (in the range of 100 nm) to facilitate margination and interaction with the endothelium. While particles used as nanoharvesting agents in proteomics or genomics analysis should have a radius close to the critical value to minimize margination and increase their circulation time.169Brigger, I.; Dubernet, C.; Couvreur, P. Nanoparticles in Cancer Therapy and Diagnosis. Adv. Drug Delivery Rev. 2002, 54, 631– 651, DOI: 10.1016/S0169-409X(02)00044-3[Crossref], [PubMed], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmsVeqtrs%253D&md5=cac7e471c5141dfa0ad4972789b47b91Nanoparticles in cancer therapy and diagnosisBrigger, Irene; Dubernet, Catherine; Couvreur, PatrickAdvanced Drug Delivery Reviews (2002), 54 (5), 631-651CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science B.V.)A review. Numerous investigations have shown that both tissue and cell distribution profiles of anticancer drugs can be controlled by their entrapment in submicronic colloidal systems (nanoparticles). The rationale behind this approach is to increase antitumor efficacy, while reducing systemic side-effects. This review provides an update of tumor targeting with conventional or long-circulating nanoparticles. The in vivo fate of these systems, after intravascular or tumoral administration, is discussed, as well as the mechanism involved in tumor regression. Nanoparticles are also of benefit for the selective delivery of oligonucleotides to tumor cells. Moreover, certain types of nanoparticles showed some interesting capacity to reverse MDR resistance, which is a major problem in chemotherapy. The first expts., aiming to decorate nanoparticles with mol. ligand for 'active' targeting of cancerous cells, are also discussed here. The last part of this review focus on the application of nanoparticles in imaging for cancer diagnosis.170Higgins, L. J.; Pomper, M. G. The Evolution of Imaging in Cancer: Current State and Future Challenges. Semin. Oncol. 2011, 38, 3– 15, DOI: 10.1053/j.seminoncol.2010.11.010[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M3jtVSmtw%253D%253D&md5=0b129635cc60a5d7e6177a76bb8c227aThe evolution of imaging in cancer: current state and future challengesHiggins Luke J; Pomper Martin GSeminars in oncology (2011), 38 (1), 3-15 ISSN:.Molecular imaging allows for the remote, noninvasive sensing and measurement of cellular and molecular processes in living subjects. Drawing upon a variety of modalities, molecular imaging provides a window into the biology of cancer from the subcellular level to the patient undergoing a new, experimental therapy. As signal transduction cascades and protein interaction networks become clarified, an increasing number of relevant targets for cancer therapy--and imaging--become available. Although conventional imaging is already critical to the management of patients with cancer, molecular imaging will provide even more relevant information, such as early detection of changes with therapy, identification of patient-specific cellular and metabolic abnormalities, and the disposition of therapeutic, gene-tagged cells throughout the body--all of which will have a considerable impact on morbidity and mortality. This overview discusses molecular imaging in oncology, providing examples from a variety of modalities, with an emphasis on emerging techniques for translational imaging.171Rudin, M.; Rausch, M.; Stoeckli, M. Molecular Imaging in Drug Discovery and Development: Potential and Limitations of Nonnuclear Methods. Mol. Imaging Biol. 2005, 7, 5– 13, DOI: 10.1007/s11307-004-0954-z[Crossref], [PubMed], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M3mvFKktA%253D%253D&md5=d2ebc16692644729abd97b08db0addb9Molecular imaging in drug discovery and development: potential and limitations of nonnuclear methodsRudin Markus; Rausch Martin; Stoeckli MarkusMolecular imaging and biology (2005), 7 (1), 5-13 ISSN:1536-1632.Noninvasive conventional imaging methods are established technologies in modern drug discovery and development providing valuable morphological, physiological, and metabolic information to characterize disease phenotypes, to evaluate the efficacy of therapy and to identify and develop potential biomarkers for clinical drug evaluation. The development of target-specific or molecular imaging has added a new dimension: molecular events such as the target expression, the drug-target interaction, or the activation of signal transduction pathways can be studied in the intact organism with high spatial and temporal resolution. Molecular imaging is inherently a multimodality approach. In this article, we review the role of molecular imaging for drug discovery and development focusing on nonnuclear imaging methods, i.e., magnetic resonance imaging (MRI) and optical imaging techniques based on fluorescence and bioluminescence readouts. Examples discussed are direct visualization of target expression using target-specific ligands or reporter genes, pathway imaging, and cell-trafficking studies.172Kopelman, R.; Lee Koo, Y. E.; Philbert, M.; Moffat, B. A.; Ramachandra Reddy, G.; McConville, P.; Hall, D. E.; Chenevert, T. L.; Bhojani, M. S.; Buck, S. M.; Rehemtulla, A.; Ross, B. D. Multifunctional Nanoparticle Platforms for in Vivo MRI Enhancement and Photodynamic Therapy of a Rat Brain Cancer. J. Magn. Magn. Mater. 2005, 293, 404– 410, DOI: 10.1016/j.jmmm.2005.02.061[Crossref], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXktVagsLw%253D&md5=52521220b800501f8fa2ebe5dffae254Multifunctional nanoparticle platforms for in vivo MRI enhancement and photodynamic therapy of a rat brain cancerKopelman, Raoul; Koo, Yong-Eun Lee; Philbert, Martin; Moffat, Bradford A.; Ramachandra Reddy, G.; McConville, Patrick; Hall, Daniel E.; Chenevert, Thomas L.; Bhojani, Mahaveer Swaroop; Buck, Sarah M.; Rehemtulla, Alnawaz; Ross, Brian D.Journal of Magnetism and Magnetic Materials (2005), 293 (1), 404-410CODEN: JMMMDC; ISSN:0304-8853. (Elsevier B.V.)A paradigm for brain cancer detection, treatment, and monitoring is established. Multifunctional biomedical nanoparticles (30-60 nm) contg. photosensitizer externally deliver reactive oxygen species (ROS) to cancer cells while simultaneously enhancing magnetic resonance imaging (MRI) contrast providing real-time tumor kill measurement. Plasma residence time control and specific cell targeting are achieved. A 5 min treatment in rats halted and even reversed in vivo tumor growth after 3-4 days post-treatment.173Abouelmagd, S. A.; Hyun, H.; Yeo, Y. Extracellularly Activatable Nanocarriers for Drug Delivery to Tumors. Expert Opin. Drug Delivery 2014, 11, 1601– 1618, DOI: 10.1517/17425247.2014.930434[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1eju7%252FI&md5=ca068dddf7992125d0a18b7e3f1e83baExtracellularly activatable nanocarriers for drug delivery to tumorsAbouelmagd, Sara A.; Hyun, Hyesun; Yeo, YoonExpert Opinion on Drug Delivery (2014), 11 (10), 1601-1618CODEN: EODDAW; ISSN:1742-5247. (Informa Healthcare)Introduction: Nanoparticles (NPs) for drug delivery to tumors need to satisfy two seemingly conflicting requirements: they should maintain phys. and chem. stability during circulation and be able to interact with target cells and release the drug at desired locations with no substantial delay. The unique microenvironment of tumors and externally applied stimuli provide a useful means to maintain a balance between the two requirements. Areas covered: We discuss nanoparticulate drug carriers that maintain stable structures in normal conditions but respond to stimuli for the spatiotemporal control of drug delivery. We first define the desired effects of extracellular activation of NPs and frequently used stimuli and then review the examples of extracellularly activated NPs. Expert opinion: Several challenges remain in developing extracellularly activatable NPs. First, some of the stimuli-responsive NPs undergo incremental changes in response to stimuli, losing circulation stability. Second, the applicability of stimuli in clin. settings is limited due to the occasional occurrence of the activating conditions in normal tissues. Third, the construction of stimuli-responsive NPs involves increasing complexity in NP structure and prodn. methods. Future efforts are needed to identify new targeting conditions and increase the contrast between activated and nonactivated NPs while keeping the prodn. methods simple and scalable.174Misri, R.; Meier, D.; Yung, A. C.; Kozlowski, P.; Häfeli, U. O. Development and Evaluation of a Dual-Modality (MRI/SPECT) Molecular Imaging Bioprobe. Nanomedicine 2012, 8, 1007– 1016, DOI: 10.1016/j.nano.2011.10.013[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVymt7rO&md5=0ecd316cf779de554fa192b15e789b29Development and evaluation of a dual-modality (MRI/SPECT) molecular imaging bioprobeMisri, Ripen; Meier, Dominik; Yung, Andrew C.; Kozlowski, Piotr; Hafeli, Urs O.Nanomedicine (New York, NY, United States) (2012), 8 (6), 1007-1016CODEN: NANOBF; ISSN:1549-9634. (Elsevier)Specific bioprobes for single photon emission computed tomog. (SPECT) and magnetic resonance imaging (MRI) have enormous potential for use in cancer imaging in near-future clin. settings. The authors describe the development of dual modality mol. imaging bioprobes, in the form of magnetic nanoparticles (NPs) conjugated to antibodies, for SPECT and MRI of mesothelin-expressing cancers. The bioprobes were developed by conjugating 111In labeled antimesothelin antibody mAbMB to superparamagnetic iron oxide NPs. Our exptl. findings provide evidence that such bioprobes retain their magnetic properties as well as the ability to specifically localize in mesothelin-expressing tumors. It is anticipated that combining SPECT with MR will help obtain both functional and anatomical imaging information with high signal sensitivity and contrast, thereby providing a powerful diagnostic tool for early diagnosis and treatment planning of mesothelin-expressing cancers. This team of investigators presents a dual-modality functionalized contrast material that enables tumor visualization both via MRI and SPECT. Similar systems are likely to be utilized in future cancer research.175Yim, H.; Seo, S.; Na, K. MRI Contrast Agent-Based Multifunctional Materials: Diagnosis and Therapy. J. Nanomater. 2011, 2011, 1, DOI: 10.1155/2011/747196176Jerjes, W.; Upile, T.; Hamdoon, Z.; Nhembe, F.; Bhandari, R.; Mackay, S.; Shah, P.; Mosse, C. A.; AS Brookes, J.; Morley, S.; Hopper, C. Ultrasound-Guided Photodynamic Therapy for Deep Seated Pathologies: Prospective Study. Lasers Surg. Med. 2009, 41, 612– 621, DOI: 10.1002/lsm.20853[Crossref], [PubMed], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MnpvVWktQ%253D%253D&md5=db0528cd9bc7747a18f199e2161b6f29Ultrasound-guided photodynamic therapy for deep seated pathologies: prospective studyJerjes Waseem; Upile Tahwinder; Hamdoon Zaid; Nhembe Farai; Bhandari Rishi; Mackay Sorcha; Shah Priya; Mosse Charles Alexander; Brookes Jocelyn A S; Morley Simon; Hopper ColinLasers in surgery and medicine (2009), 41 (9), 612-21 ISSN:.INTRODUCTION: Interstitial photodynamic therapy remains an attractive remedial option in minimally invasive surgery. Our aim in this prospective study was to evaluate the outcome following ultrasound-guided iPDT of deep-seated pathologies. Patients' reports on quality of life with clinical and radiological evaluation were the main end point parameters used to assess the outcome. MATERIALS AND METHODS: Sixty-eight patients were referred to the UCLH Head and Neck Centre for treatment of various deep-seated pathologies involving the head and neck region, upper and lower limbs. All patients underwent interstitial photodynamic therapy under general anaesthesia, using 0.15 mg/kg mTHPC as the photosensitising agent. Following treatment, patients were followed-up for a mean of 7 months. RESULTS: All three patients who presented with visual problems reported improvement after treatment. Also, 14/17 patients reported improvement of breathing. Improvement of swallowing was reported by 25/30 patients; while speaking improvement was evident in 16/22 patients and 33/40 reported reduction in the disfigurement caused by their pathology. All five patients with impeded limb function reported some degree of improvement. Clinical assessment showed that half of the patients had 'good response' to the treatment and a third reported 'moderate response' with two patients being free of disease. Radiological assessment comparing imaging 6-week post-PDT to the baseline showed stable pathology with no change in size in 13 patients, minimal response in 18 patients, moderate response in 23 patients and significant response in 11 patients. CONCLUSION: This study on 68 patients with deep-seated pathologies undergoing interstitial photodynamic therapy provided evidence that PDT can be the fourth modality in the management of tissue disease.177Eljamel, M. S.; Goodman, C.; Moseley, H. ALA and Photofrin Fluorescence-Guided Resection and Repetitive PDT in Glioblastoma Multiforme: A Single Centre Phase III Randomised Controlled Trial. Lasers Med. Sci. 2008, 23, 361– 367, DOI: 10.1007/s10103-007-0494-2[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cnis1Cntg%253D%253D&md5=8d9f26ebe7e1d8d3bc5bc5a68757fa44ALA and Photofrin fluorescence-guided resection and repetitive PDT in glioblastoma multiforme: a single centre Phase III randomised controlled trialEljamel M Sam; Goodman Carol; Moseley HarryLasers in medical science (2008), 23 (4), 361-7 ISSN:0268-8921.Glioblastoma multiforme (GBM) carries dismal prognosis and cannot be eradicated surgically because of its wide brain invasion. The objective of this prospective randomised controlled trial was to evaluate ALA and Photofrin fluorescence-guided resection (FGR) and repetitive photodynamic therapy (PDT) in GBM. We recruited 27 patients; 13 were in the study group and 14 were in the control group. The mean survival of the study group was 52.8 weeks compared to 24.6 weeks in the control group (p<0.01). The study group gained on average 20 points on the Karnofsky performance score (p<0.05). There were no differences in complications or hospital stay between the two groups. The mean time to tumour progression was 8.6 months in the study group compared to 4.8 months in the control group (p<0.05). Therefore, ALA and Photofrin fluorescence-guided resection and repetitive PDT offered a worthwhile survival advantage without added risk to patients with GBM. A multicentre randomized controlled trial is warranted to confirm these results.178Mark, J. R.; Gelpi-Hammerschmidt, F.; Trabulsi, E. J.; Gomella, L. G. Blue Light Cystoscopy for Detection and Treatment of Non-Muscle Invasive Bladder Cancer. Can. J. Urol. 2012, 19, 6227– 6231[PubMed], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38rmtVequg%253D%253D&md5=0e67a37ffbd58c696e45864cfb8a6abeBlue light cystoscopy for detection and treatment of non-muscle invasive bladder cancerMark J Ryan; Gelpi-Hammerschmidt Francisco; Trabulsi Edouard J; Gomella Leonard GThe Canadian journal of urology (2012), 19 (2), 6227-31 ISSN:1195-9479.In patients with non-muscle invasive bladder cancer, fluorescence cystoscopy can improve the detection and ablation of bladder tumors. In this paper we describe the technique and practical aspects of hexaminolevulinate (HAL) fluorescence cystoscopy, also known as "blue light cystoscopy".179Mallidi, S.; Spring, B. Q.; Chang, S.; Vakoc, B.; Hasan, T. Optical Imaging, Photodynamic Therapy and Optically Triggered Combination Treatments. Cancer J. (Philadelphia, PA, U. S.) 2015, 21, 194– 205, DOI: 10.1097/PPO.0000000000000117[Crossref], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpvV2qsLk%253D&md5=ad5c6efd2cb629c90e146acea94c1714Optical Imaging, Photodynamic Therapy and Optically Triggered Combination TreatmentsMallidi, Srivalleesha; Spring, Bryan Q.; Chang, Sung; Vakoc, Benjamin; Hasan, TayyabaCancer Journal (Philadelphia, PA, United States) (2015), 21 (3), 194-205CODEN: CAJOCB; ISSN:1528-9117. (Lippincott Williams & Wilkins)A review. Optical imaging is becoming increasingly promising for real-time image-guided resections, and combined with photodynamic therapy (PDT), a photochem.-based treatment modality, optical approaches can be intrinsically "theranostic.". Challenges in PDT include precise light delivery, dosimetry, and photosensitizer tumor localization to establish tumor selectivity, and like all other modalities, incomplete treatment and subsequent activation of mol. escape pathways are often attributable to tumor heterogeneity. Key advances in mol. imaging, target-activatable photosensitizers, and optically active nanoparticles that provide both cytotoxicity and a drug release mechanism have opened exciting avenues to meet these challenges. The focus of the review is optical imaging in the context of PDT, but the general principles presented are applicable to many of the conventional approaches to cancer management. We highlight the role of optical imaging in providing structural, functional, and mol. information regarding photodynamic mechanisms of action, thereby advancing PDT and PDT-based combination therapies of cancer. These advances represent a PDT renaissance with increasing applications of clin. PDT as a frontline cancer therapy working in concert with fluorescence-guided surgery, chemotherapy, and radiation.180Mallidi, S.; Anbil, S.; Lee, S.; Manstein, D.; Elrington, S.; Kositratna, G.; Schoenfeld, D.; Pogue, B.; Davis, S. J.; Hasan, T. Photosensitizer Fluorescence and Singlet Oxygen Luminescence as Dosimetric Predictors of Topical 5-Aminolevulinic Acid Photodynamic Therapy Nduced Clinical Erythema. J. Biomed. Opt. 2014, 19, 028001, DOI: 10.1117/1.JBO.19.2.028001[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXosVyntrc%253D&md5=ba85d03716a9b1d68d1bfcd644d7e19cPhotosensitizer fluorescence and singlet oxygen luminescence as dosimetric predictors of topical 5-aminolevuliniv acid photodynamic therapy induced clinical erythemaMallidi, Srivalleesha; Anbil, Sriram; Lee, Seonkyung; Manstein, Dieter; Elrington, Stefan; Kositratna, Garuna; Schoenfeld, David; Pogue, Brian; Davis, Steven J.; Hasan, TayyabaJournal of Biomedical Optics (2014), 19 (2), 028001/1-028001/13CODEN: JBOPFO; ISSN:1083-3668. (Society of Photo-Optical Instrumentation Engineers)The need for patient-specific photodynamic therapy (PDT) in dermatol. and oncol. applications has triggered several studies that explore the utility of surrogate parameters as predictive reporters of treatment outcome. Although photosensitizer (PS) fluorescence, a widely used parameter, can be viewed as emission from several fluorescent states of the PS (e.g., minimally aggregated and monomeric), we suggest that singlet oxygen luminescence (SOL) indicates only the active PS component responsible for the PDT. Here, the ability of discrete PS fluorescence-based metrics (abs. and percent PS photobleaching and PS re-accumulation post-PDT) to predict the clin. phototoxic response (erythema) resulting from 5-aminolevulinic acid PDT was compared with discrete SOL (DSOL)-based metrics (DSOL counts pre-PDT and change in DSOL counts pre/post-PDT) in healthy human skin. Receiver operating characteristic curve (ROC) analyses demonstrated that abs. fluorescence photobleaching metric (AFPM) exhibited the highest area under the curve (AUC) of all tested parameters, including DSOL based metrics. The combination of dose-metrics did not yield better AUC than AFPM alone. Although sophisticated real-time SOL measurements may improve the clin. utility of SOL-based dosimetry, discrete PS fluorescence-based metrics are easy to implement, and our results suggest that AFPM may sufficiently predict the PDT outcomes and identify treatment nonresponders with high specificity in clin. contexts.181Zhou, X.; Pogue, B. W.; Chen, B.; Demidenko, E.; Joshi, R.; Hoopes, J.; Hasan, T. Pretreatment Photosensitizer Dosimetry Reduces Variation in Tumor Response. Int. J. Radiat. Oncol., Biol., Phys. 2006, 64, 1211– 1220, DOI: 10.1016/j.ijrobp.2005.11.019[Crossref], [PubMed], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xhslyis7k%253D&md5=eb846ddad5549ae5f31580258c3ef873Pretreatment photosensitizer dosimetry reduces variation in tumor responseZhou, Xiaodong; Pogue, Brian W.; Chen, Bin; Demidenko, Eugene; Joshi, Rohan; Hoopes, Jack; Hasan, TayyabaInternational Journal of Radiation Oncology, Biology, Physics (2006), 64 (4), 1211-1220CODEN: IOBPD3; ISSN:0360-3016. (Elsevier Inc.)Photosensitizer uptake variation in photodynamic therapy (PDT) compensates via control of delivered light dose through photodynamic dose calcn. based on online dosimetry of photosensitizer in tissue before treatment. Photosensitizer verteporfin was quantified via multiple fluorescence microprobe measurements immediately before treatment. To compensate individual PDT treatments, photodynamic doses were calcd. on an individual animal basis, by matching the light delivered to provide an equal photosensitizer dose multiplied by light dose. This was completed for the lower quartile, median, and upper quartile of the photosensitizer distribution. PDT-induced tumor responses were evaluated by the tumor regrowth assay. Verteporfin uptake varied considerably among tumors and within a tumor. The coeff. of variation in the surviving fraction was found significantly decreased in groups compensated to the lower quartile (CL-PDT), the median (CM-PDT), and the upper quartile (CU-PDT) of photosensitizer distribution. The CL-PDT group was significantly less effective compared with NC-PDT (Noncompensated PDT), CM-PDT, and CU-PDT treatments. No significant difference in effectiveness was obsd. between NC-PDT, CM-PDT, and CU-PDT treatment groups. This research suggests that accurate quantification of tissue photosensitizer levels and subsequent adjustment of light dose will allow for reduced subject variation and improved treatment consistency.182Zou, J.; Yin, Z.; Wang, P.; Chen, D.; Shao, J.; Zhang, Q.; Sun, L.; Huang, W.; Dong, X. Photosensitizer Synergistic Effects: D-A-D Structured Organic Molecule With Enhanced Fluorescence and Singlet Oxygen Quantum Yield for Photodynamic Therapy. Chem. Sci. 2018, 9, 2188– 2194, DOI: 10.1039/C7SC04694D[Crossref], [PubMed], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFOitLc%253D&md5=e4dcd13bbd81c17fe3266ffaa1dccd94Photosensitizer synergistic effects: D-A-D structured organic molecule with enhanced fluorescence and singlet oxygen quantum yield for photodynamic therapyZou, Jianhua; Yin, Zhihui; Wang, Peng; Chen, Dapeng; Shao, Jinjun; Zhang, Qi; Sun, Liguo; Huang, Wei; Dong, XiaochenChemical Science (2018), 9 (8), 2188-2194CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The development of photosensitizers with high fluorescence intensity and singlet oxygen (1O2) quantum yields (QYs) is of great importance for cancer diagnosis and photodynamic therapy (PDT). Diketopyrrolopyrrole (DPP) and boron dipyrromethene (BODIPY) are two kinds of building block with great potential for PDT. Herein, a novel donor-acceptor-donor (D-A-D) structured org. photosensitizer DPPBDPI with a benzene ring as a p bridge linking DPP and BODIPY has been designed and synthesized. The results indicate that the combination of DPP with BODIPY can simultaneously increase the fluorescence QY (5.0%) and the 1O2 QY (up to 80%) significantly by the synergistic effect of the two photosensitizers. By nanopptn., DPPBDPI can form uniform nanoparticles (NPs) with a diam. of less than 100 nm. The obtained NPs not only exhibit high photo-toxicity, but also present negligible dark toxicity towards HeLa cells, demonstrating their excellent photodynamic therapeutic efficacy. In vivo fluorescence imaging shows that DPPBDPI NPs can target the tumor site quickly with the enhanced permeability and retention (EPR) effect and can effectively inhibit tumor growth using photodynamic therapy even with low doses (0.5 mg kg-1). The enhanced imaging and photodynamic performance of DPPBDPI suggest that the synergistic effect of DPP and BODIPY provides a novel theranostic platform for cancer diagnosis and photodynamic therapy.183Pereira, N. A. M.; Laranjo, M.; Casalta-Lopes, J.; Serra, A. C.; Piñeiro, M.; Pina, J.; Seixas de Melo, J. S.; Senge, M. O.; Botelho, M. F.; Martelo, L.; Burrows, H. D.; Pinho E Melo, T. M. V. D. Platinum(II) Ring-Fused Chlorins as Near-Infrared Emitting Oxygen Sensors and Photodynamic Agents. ACS Med. Chem. Lett. 2017, 8, 310– 315, DOI: 10.1021/acsmedchemlett.6b00476[ACS Full Text], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjt1Wltr0%253D&md5=77b58a23768f743c859a19a3a3ebec40Platinum(II) Ring-Fused Chlorins as Near-Infrared Emitting Oxygen Sensors and Photodynamic AgentsPereira, Nelson A. M.; Laranjo, Mafalda; Casalta-Lopes, Joao; Serra, Armenio C.; Pineiro, Marta; Pina, Joao; Seixas de Melo, J. Sergio; Senge, Mathias O.; Botelho, M. Filomena; Martelo, Liliana; Burrows, Hugh D.; Pinho e Melo, Teresa M. V. D.ACS Medicinal Chemistry Letters (2017), 8 (3), 310-315CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Novel near-IR luminescent compds. based on platinum(II) 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins are described. These compds. have high photostability and display light emission, in particular simultaneous fluorescence and phosphorescence emission in soln. at room temp., in the biol. relevant 700-850 nm red and near-IR (NIR) spectral region, making them excellent materials for biol. imaging. The simultaneous presence of fluorescence and phosphorescence emission at room temp., with the phosphorescence strongly quenched by oxygen whereas fluorescence remains unaffected, allows these compds. to be used as ratiometric oxygen sensors in chem. and biol. media. Both steady-state (fluorescence vs. phosphorescence intensities) and dynamic (dependence of phosphorescence lifetimes upon oxygen concn.) luminescence approaches can be used. Photocytotoxicity studies against human melanocytic melanoma cells (A375) indicate that these compds. display potential as photosensitizers in photodynamic therapy.184Stefflova, K.; Chen, J.; Zheng, G. Using Molecular Beacons for Cancer Imaging and Treatment. Front. Biosci., Landmark Ed. 2007, 12, 4709– 4721, DOI: 10.2741/2420[Crossref], [PubMed], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXms1KltL4%253D&md5=8c5386aa2557ff3d9173e535b1abda12Using molecular beacons for cancer imaging and treatmentStefflova, Klara; Chen, Juan; Zheng, GangFrontiers in Bioscience (2007), 12 (), 4709-4721CODEN: FRBIF6; ISSN:1093-4715. (Frontiers in Bioscience)A review. Mol. beacons are essentially all probes that illuminate particular cellular target or cells with similar characteristics. In this review we focus on those mol. beacons that use near-IR fluorescence imaging (NIRF-I) to identify the unique cellular and metabolic markers characteristic of cancer. They employ various delivery and activation pathways, selectively or specifically targeting proliferating and immortal cancer cells. These beacons can either be used in an imaging step sep. from therapy or they can intimately connect these two steps into a single process. Matching cancer therapy to NIRF-I is photodynamic therapy (PDT) that uses the light-triggered phototoxic properties of some porphyrin-based dyes. Guided by beacon's restored fluorescence, the PDT laser could be focused on affected sites, killing the cancer cells using the enhanced photoactivity of the same beacon. Or vice versa-the restored fluorescence from the cleaved beacon could be used as an indication of the beacon's own therapeutic success, imaging the post-PDT apoptotic cells.185Pineiro, M.; Pereira, M. M.; Rocha Gonsalves, A. M. D. A.; Arnaut, L. G.; Formosinho, S. J. Singlet Oxygen Quantum Yields From Halogenated Chlorins: Potential New Photodynamic Therapy Agents. J. Photochem. Photobiol., A 2001, 138, 147– 157, DOI: 10.1016/S1010-6030(00)00382-8[Crossref], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhtlCqtLw%253D&md5=8eb00d9fb67c4ee0cc18a3d6064c77acSinglet oxygen quantum yields from halogenated chlorins: potential new photodynamic therapy agentsPineiro, Marta; Pereira, Mariette M.; Gonsalves, A. M. d'A. Rocha; Arnaut, Luis G.; Formosinho, Sebastiao J.Journal of Photochemistry and Photobiology, A: Chemistry (2001), 138 (2), 147-157CODEN: JPPCEJ; ISSN:1010-6030. (Elsevier Science S.A.)Flash photolysis and photoacoustic calorimetry were used to measure the energy-transfer rates and singlet oxygen quantum yields originated by the triplet states of halogenated tetrakisphenylporphyrins and related chlorins in aerated toluene. The chlorins (λmax ≈ 660 nm, ε ≈ 3 × 104 M-1-cm-1) have long-lived triplet states (> 12 μs) in the absence of mol. oxygen, and in its presence the singlet oxygen prodn. quantum yields of the 2-chloro- and 2,6-dichlorophenyl derivs. are 0.89 ± 0.05 and 0.98 ± 0.02, resp. The high absorptivity in the red, the photostability and the efficiency of these chlorins in producing singlet oxygen suggests a ground for the development of better sensitizers for photodynamic therapy.186Serra, A.; Pineiro, M.; Santos, C. I.; Rocha Gonsalves, A. M. D. A.; Abrantes, M.; Laranjo, M.; Botelho, M. F. In Vitro Photodynamic Activity of 5,15-Bis(3-Hydroxyphenyl)Porphyrin and Its Halogenated Derivatives Against Cancer Cells. Photochem. Photobiol. 2010, 86, 206– 212, DOI: 10.1111/j.1751-1097.2009.00622.x[Crossref], [PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlKms7g%253D&md5=d421afa9cc986d2120abc9b6cde75632In vitro photodynamic activity of 5,15-bis(3-hydroxyphenyl)porphyrin and its halogenated derivatives against cancer cellsSerra, Armenio; Pineiro, Marta; Santos, Catarina Isabel; Gonsalves, Antonio Manuel d'A. Rocha; Abrantes, Margarida; Laranjo, Mafalda; Botelho, Maria FilomenaPhotochemistry and Photobiology (2010), 86 (1), 206-212CODEN: PHCBAP; ISSN:0031-8655. (Wiley-Blackwell)5,15-Diarylporphyrins (1-5) with hydroxyl groups and halogens as substituents were prepd. by condensation between unsubstituted dipyrromethane and halogenated m-hydroxybenzaldehydes. Photophys. properties show that the non-halogenated porphyrin 1 has higher fluorescence yield but lower singlet oxygen formation quantum yield than the halogenated derivs. due to the heavy atom effect. The in vitro activity of these derivs. was tested against WiDr colorectal adenocarcinoma and A375 melanoma cancer cells. All porphyrins present a much higher phototoxicity than Photofrin with IC50 values lower than the 50 nM level for WiDr cells and 25 nM level for A375 cancer cells. The most photoactive compd. is the non-halogenated porphyrin 1 which also presents the highest uptake. Halogenated derivs. present much lower uptakes than 1. However, their photoactivity is similar to compd. 1 showing that their intrinsic photoactivity (ISP) is very high. Iodinated compd. 4 presents the highest ISP. The greater ability of these porphyrins to destroy cancer cells could be related to their photophys. and photochem. properties.187Serra, A. C.; Pineiro, M.; Rocha Gonsalves, A. M. d. A.; Abrantes, M.; Laranjo, M.; Santos, A. C.; Botelho, M. F. Halogen Atom Effect on Photophysical and Photodynamic Characteristics of Derivatives of 5,10,15,20-Tetrakis(3-Hydroxyphenyl)Porphyrin. J. Photochem. Photobiol., B 2008, 92, 59– 65, DOI: 10.1016/j.jphotobiol.2008.04.006[Crossref], [PubMed], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosFSktrk%253D&md5=03a8fc2a808fd2fcbdfdbfbfd1074981Halogen atom effect on photophysical and photodynamic characteristics of derivatives of 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrinSerra, A. C.; Pineiro, M.; Rocha Gonsalves, A. M. d'A.; Abrantes, M.; Laranjo, M.; Santos, A. C.; Botelho, M. F.Journal of Photochemistry and Photobiology, B: Biology (2008), 92 (1), 59-65CODEN: JPPBEG; ISSN:1011-1344. (Elsevier B.V.)Brominated and iodinated derivs. of 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin were synthesized directly from the corresponding aldehydes. Photophys. and photochem. properties, singlet oxygen formation quantum yields, photobleaching and log P were measured. Cellular uptake measurements and cytotoxicity assays on WiDr and A375 tumor cell lines were performed. 5,10,15,20-Tetrakis(2-bromo-5-hydroxyphenyl)porphyrin showed the best cytotoxicity with values of IC50 of 113 nM over WiDr cells and 52 nM over A375 cells.188Stefflova, K.; Li, H.; Chen, J.; Zheng, G. Peptide-Based Pharmacomodulation of a Cancer-Targeted Optical Imaging and Photodynamic Therapy Agent. Bioconjugate Chem. 2007, 18, 379– 388, DOI: 10.1021/bc0602578[ACS Full Text], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhs1Sqt78%253D&md5=8bf63060a689033252e06f42e0f8b4d4Peptide-Based Pharmacomodulation of a Cancer-Targeted Optical Imaging and Photodynamic Therapy AgentStefflova, Klara; Li, Hui; Chen, Juan; Zheng, GangBioconjugate Chemistry (2007), 18 (2), 379-388CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)We designed and synthesized a folate receptor-targeted, water-sol., and pharmacomodulated photodynamic therapy (PDT) agent that selectively detects and destroys the targeted cancer cells while sparing normal tissue. This was achieved by minimizing the normal organ uptake (e.g., liver and spleen) and by discriminating between tumors with different levels of folate receptor (FR) expression. This construct (Pyro-peptide-Folate, PPF) is composed of three components: (1) pyropheophorbide a (Pyro) as an imaging and therapeutic agent, (2) peptide sequence as a stable linker and modulator improving the delivery efficiency, and (3) Folate as a homing mol. targeting FR-expressing cancer cells. We obsd. an enhanced accumulation of PPF in KB cancer cells (FR+) compared to HT 1080 cancer cells (FR-), resulting in a more effective post-PDT killing of KB cells over HT 1080 or normal CHO cells. The accumulation of PPF in KB cells can be up to 70% inhibited by an excess of free folic acid. The effect of Folate on preferential accumulation of PPF in KB tumors (KB vs HT 1080 tumors 2.5:1) was also confirmed in vivo. In contrast to that, no significant difference between the KB and HT 1080 tumor was obsd. in case of the untargeted probe (Pyro-peptide, PP), eliminating the potential influence of Pyro's own nonspecific affinity to cancer cells. More importantly, we found that incorporating a short peptide sequence considerably improved the delivery efficiency of the probe-a process we attributed to a possible peptide-based pharmacomodulation-as was demonstrated by a 50-fold redn. in PPF accumulation in liver and spleen when compared to a peptide-lacking probe (Pyro-K-Folate, PKF). This approach could potentially be generalized to improve the delivery efficiency of other targeted mol. imaging and photodynamic therapy agents.189Wilson, B. C.; Van Lier, J. E. Radiolabelled Photosensitizers for Tumour Imaging and Photodynamic Therapy. J. Photochem. Photobiol., B 1989, 3, 459, DOI: 10.1016/1011-1344(89)80052-1[Crossref], [PubMed], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXkvFartLg%253D&md5=b72280d15f3fc1e0322090d2fd0d9365Radiolabelled photosensitizers for tumor imaging and photodynamic therapyWilson, B. C.; Van Lier, J. E.Journal of Photochemistry and Photobiology, B: Biology (1989), 3 (3), 459-63CODEN: JPPBEG; ISSN:1011-1344.A review, with 22 refs., of the use of photosensitizers labeled with 3H, 14C, or short-lived γ- or positron-emitting radionuclides for tumor imaging and noninvasive quantitation of photosensitizers.190Pandey, S. K.; Sajjad, M.; Chen, Y.; Zheng, X.; Yao, R.; Missert, J. R.; Batt, C.; Nabi, H. A.; Oseroff, A. R.; Pandey, R. K. Comparative Positron-Emission Tomography (PET) Imaging and Phototherapeutic Potential of 1 24i- Labeled Methyl- 3-(1’-Iodobenzyloxyethyl) Pyropheophorbide-A vs the Corresponding Glucose and Galactose Conjugates. J. Med. Chem. 2009, 52, 445– 455, DOI: 10.1021/jm8012213[ACS Full Text], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFaisrfO&md5=9e94231ac3c2b0d05a1a032887484f40Comparative Positron-Emission Tomography (PET) Imaging and Phototherapeutic Potential of 124I- Labeled Methyl- 3-(1'-iodobenzyloxyethyl)pyropheophorbide-a vs the Corresponding Glucose and Galactose ConjugatesPandey, Suresh K.; Sajjad, Munawwar; Chen, Yihui; Zheng, Xiang; Yao, Rutao; Missert, Joseph R.; Batt, Carrie; Nabi, Hani A.; Oseroff, Allan R.; Pandey, Ravindra K.Journal of Medicinal Chemistry (2009), 52 (2), 445-455CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In our present study, 3-(1'-m-iodobenzyloxyethyl)pyropheophorbide-a Me ester 1, 3-(1'-m-iodobenzyloxyethyl)-172-{(2-deoxy)glucose}pyropheophorbide-a 2, and 3-(1'-m-iodobenzyloxyethyl)-172-{(1-deoxy)galactose}pyropheophorbide-a 3 were synthesized and converted into the corresponding 124I-labeled analogs by reacting the intermediate trimethyltin analogs with Na124I. Photosensitizers 1-3 were evaluated for the PDT efficacy in C3H mice bearing RIF tumors at variable doses and showed a significant long-term tumor cure. Among the compds. investigated, the non-carbohydrate analog 1 was most effective. These results were in contrast to the in vitro data, where compared to the parent analog the corresponding galactose and glucose derivs. showed enhanced cell kill. Among the corresponding 124I-labeled analogs, excellent tumor images were obtained from compd. 1 in both tumor models (RIF and Colon-26) and the best tumor contrast was obsd. at 72 h after injection. Conjugating a glucose moiety to photosensitizer 1 initially diminished its tumor uptake, whereas with time the corresponding galactose analog showed improved tumor contrast.191Fazaeli, Y.; Jalilian, A. R.; Amini, M. M.; Ardaneh, K.; Rahiminejad, A.; Bolourinovin, F.; Moradkhani, S.; Majdabadi, A. Development of a 68Ga-Fluorinated Porphyrin Complex as a Possible PET Imaging Agent. Nucl. Med. Mol. Imaging 2012, 46, 20– 26, DOI: 10.1007/s13139-011-0109-5[Crossref], [PubMed], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XisFCksbc%253D&md5=3675ff999e45ee7ac1d1ee0eedadadf7Development of a 68Ga-Fluorinated Porphyrin Complex as a Possible PET Imaging AgentFazaeli, Yousef; Jalilian, Amir R.; Amini, Mostafa M.; Ardaneh, Khosro; Rahiminejad, Ali; Bolourinovin, Fatemeh; Moradkhani, Sedigheh; Majdabadi, AbbasNuclear Medicine and Molecular Imaging (2012), 46 (1), 20-26CODEN: NMMIB8; ISSN:1869-3482. (Springer)Aim Due to the interesting pharmacol. properties of porphyrins, the idea of developing a possible tumor imaging agent using PET by incorporating 68Ga into a suitable porphyrin ligand was investigated. Methods 68Ga-labeled 5,10,15,20-tetrakis(pentafluoro-13 phenyl) porphyrin (68Ga-TFPP) was prepd. using freshly eluted [68Ga]GaCl3 obtained from a 68Ge/68Ga generator developed inhouse and 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (H2TFPP) for 60 min at 100°C. Results The complex was prepd. with high radiochem. purity (>99% ITLC, >99% HPLC, specific activity: 13-14 GBq/mmol). Stability of the complex was checked in the final formulation and in human serum for 5 h. The partition coeff. was calcd. for the compd. (log P = 0.62). The biodistribution of the labeled compd. in vital organs of Swiss mice bearing fibrosarcoma tumors was studied using scarification studies and SPECT imaging up to 1 h. The complex was mostly washed out from the circulation through kidneys and liver. The tumor-to-muscle ratio 1 h post injection was 5.13. Conclusion The radiolabeled porphyrin complex demonstrated potential for further imaging studies in other tumor models.192Shi, J.; Liu, T. W. B.; Chen, J.; Green, D.; Jaffray, D.; Wilson, B. C.; Wang, F.; Zheng, G. Transforming a Targeted Porphyrin Theranostic Agent into a PET Imaging Probe for Cancer. Theranostics 2011, 1, 363– 370, DOI: 10.7150/thno/v01p0363[Crossref], [PubMed], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XislaltLY%253D&md5=713db4a73f97eebb1067d39ef50a8494Transforming a targeted porphyrin theranostic agent into a PET imaging probe for cancerShi, Jiyun; Liu, Tracy W. B.; Chen, Juan; Green, David; Jaffray, David; Wilson, Brian C.; Wang, Fan; Zheng, GangTheranostics (2011), 1 (), 363-370CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)Porphyrin based photosensitizers are useful agents for photodynamic therapy (PDT) and fluorescence imaging of cancer. Porphyrins are also excellent metal chelators forming highly stable metallo-complexes making them efficient delivery vehicles for radioisotopes. Here we investigated the possibility of incorporating 64Cu into a porphyrin-peptide-folate (PPF) probe developed previously as folate receptor (FR) targeted fluorescent/PDT agent, and evaluated the potential of turning the resulting 64Cu-PPF into a positron emission tomog. (PET) probe for cancer imaging. Noninvasive PET imaging followed by radioassay evaluated the tumor accumulation, pharmacokinetics and biodistribution of 64Cu-PPF. 64Cu-PPF uptake in FR-pos. tumors was visible on small-animal PET images with high tumor-to-muscle ratio (8.88 ± 3.60) obsd. after 24 h. Competitive blocking studies confirmed the FR-mediated tracer uptake by the tumor. The ease of efficient 64Cu-radiolabeling of PPF while retaining its favorable biodistribution, pharmacokinetics and selective tumor uptake, provides a robust strategy to transform tumor-targeted porphyrin-based photosensitizers into PET imaging probes.193Tamura, K.; Kurihara, H.; Yonemori, K.; Tsuda, H.; Suzuki, J.; Kono, Y.; Honda, N.; Kodaira, M.; Yamamoto, H.; Yunokawa, M.; Shimizu, C.; Hasegawa, K.; Kanayama, Y.; Nozaki, S.; Kinoshita, T.; Wada, Y.; Tazawa, S.; Takahashi, K.; Watanabe, Y.; Fujiwara, Y. 64Cu-DOTA-Trastuzumab PET Imaging in Patients with HER2-Positive Breast Cancer. J. Nucl. Med. 2013, 54, 1869– 1875, DOI: 10.2967/jnumed.112.118612[Crossref], [PubMed], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVClsrzN&md5=a91a6e5dd49d623379d7976e128a70bf64Cu-DOTA-trastuzumab PET imaging in patients with HER2-positive breast cancerTamura, Kenji; Kurihara, Hiroaki; Yonemori, Kan; Tsuda, Hitoshi; Suzuki, Junko; Kono, Yuzuru; Honda, Natsuki; Kodaira, Makoto; Yamamoto, Harukaze; Yunokawa, Mayu; Shimizu, Chikako; Hasegawa, Koki; Kanayama, Yousuke; Nozaki, Satoshi; Kinoshita, Takayuki; Wada, Yasuhiro; Tazawa, Shusaku; Takahashi, Kazuhiro; Watanabe, Yasuyoshi; Fujiwara, YasuhiroJournal of Nuclear Medicine (2013), 54 (11), 1869-1875CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)The purpose of this study was to det. the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)-pos. tumor images of 64Cu-DOTA-trastuzumab in humans. Methods: PET was performed on 6 patients with primary or metastatic HER2-pos. breast cancer at 1, 24, and 48 h after injection of approx. 130 MBq of the probe 64Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of 64Cu-DOTA-trastuzumab and during the 1-wk follow-up period. Results: According to our results, the best timing for the assessment of 64Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during 64Cu-DOTA-trastuzumab PET was equiv. to that during conventional 18F-FDG PET. The radioactivity in the blood was high, but uptake of 64Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, 64Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood-brain barrier disruptions. In 3 patients, 64Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. Conclusion: The findings of this study indicated that 64Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-pos. lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacol. safety results were acceptable at the dose required for adequate PET imaging.194Aguilar-Ortíz, E.; Jalilian, A. R.; Ávila-Rodríguez, M. A. Porphyrins as Ligands for 64Copper: Background and Trends. MedChemComm 2018, 9, 1577– 1588, DOI: 10.1039/C8MD00263K[Crossref], [PubMed], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFeqt7rE&md5=b85d1917c4841a0ed67197c7c64e99ccPorphyrins as ligands for 64copper: background and trendsAguilar-Ortiz, Edgar; Jalilian, Amir R.; Avila-Rodriguez, Miguel A.MedChemComm (2018), 9 (10), 1577-1588CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Porphyrins and 64Cu have emerged as a novel synergic option for applications in PET mol. imaging. Both the characteristics and photophys. properties of macrocyclic porphyrins and the relatively long half-life of the copper isotope, in addn. to the increased tumor-specific uptake of porphyrins compared to normal cells, make this complex an attractive option not only for diagnosis but also for therapeutic applications. Herein, we present an overview of the latest results on the development of PET agents based on porphyrins and 64Cu, including methods used to improve the selectivity of these macrocycles when conjugated with biol. units such as monoclonal antibodies, peptides or proteins.195Moran, M.; MacDonald, T.; Liu, T.; Forbes, J.; Zhen, G.; Valliant, J. Copper-64-Labeled Porphysomes for PET Imaging. J. Nucl. Med. 2014, 55, 1016196Rousseau, J.; Ali, H.; Lamoureux, G.; Lebel, E.; Van Lier, J. E. Synthesis, Tissue Distribution and Tumor Uptake of 99mTc- and 67Ga- Tetrasulfophthalocyanine. Int. J. Appl. Radiat. Isot. 1985, 36, 709– 716, DOI: 10.1016/0020-708X(85)90041-9[Crossref], [PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXlslClurY%253D&md5=0ba8ebfeec5dd08a43c15449df9af940Synthesis, tissue distribution and tumor uptake of technetium-99m and gallium-67 tetrasulfophthalocyanineRousseau, Jacques; Ali, Hasrat; Lamoureux, Guy; Lebel, Etienne; Van Lier, Johan E.International Journal of Applied Radiation and Isotopes (1985), 36 (9), 709-16CODEN: IJARAY; ISSN:0020-708X.Complexes of tetrasulfophthalocyanine with 99mTc(I), 69Ga, and 67Ga (II) were prepd. by the condensation of sulfophthalic acid with the appropriate metal species. The Ga-complex was also obtained by exchange of the central H atoms of the empty tetrasulfophthalocyanine. The labeled complexes were purified by TLC and characterized by their chromatog. properties. In rabbits and tumor-bearing rats, most of the radioactivity accumulated in the kidneys, liver, ovaries, adrenals, and spleen. Comparison of these distribution patterns with those of 99mTcO4- and 67Ga citrate confirmed the in vivo stability of the labeled complexes. The 67Ga complex reached better tumor-to-blood and tumor-to-muscle ratios than 67Ga citrate.197Li, Z.; Lin, T. P.; Liu, S.; Huang, C. W.; Hudnall, T. W.; Gabbaï, F. P.; Conti, P. S. Rapid Aqueous [18F]-Labeling of a BODIPY Dye for Positron Emission Tomography/Fluorescence Dual Modality Imaging. Chem. Commun. 2011, 47, 9324– 9326, DOI: 10.1039/c1cc13089g[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpvFyksbs%253D&md5=b617f7ac098d9f10c57a46ca434cb277Rapid aqueous [18F]-labeling of a bodipy dye for positron emission tomography/fluorescence dual modality imagingLi, Zibo; Lin, Tzu-Pin; Liu, Shuanglong; Huang, Chiun-Wei; Hudnall, Todd W.; Gabbai, Francois P.; Conti, Peter S.Chemical Communications (Cambridge, United Kingdom) (2011), 47 (33), 9324-9326CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)We report the rapid nucleophilic [18F]-radiolabeling of a bodipy dye in aq. solns. This radiolabeled dye, whose biodistribution and clearance has been studied in mice, is stable in vivo and can be used as a positron emission tomog./fluorescence dual modality imaging agent.198Pandey, R. K.; Goswami, L. N.; Chen, Y.; Gryshuk, A.; Missert, J. R.; Oseroff, A.; Dougherty, T. J. Nature: A Rich Source for Developing Multifunctional Agents. Tumor-Imaging and Photodynamic Therapy. Lasers Surg. Med. 2006, 38, 445– 467, DOI: 10.1002/lsm.20352[Crossref], [PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28zosFCnuw%253D%253D&md5=4d6da90479d36b451478771987e0ab09Nature: a rich source for developing multifunctional agents. Tumor-imaging and photodynamic therapyPandey Ravindra K; Goswami Lalit N; Chen Yihui; Gryshuk Amy; Missert Joseph R; Oseroff Allan; Dougherty Thomas JLasers in surgery and medicine (2006), 38 (5), 445-67 ISSN:0196-8092.The purpose of this review is to call attention in the use of chlorophyll-a and bacteriochlorophyll-a to develop more than 600 photosensitizers (lambda (max) 660 nm-800 nm) during the last 15 years (1990-2005) at the Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo. This article mainly includes the chemistry, preclinical results, and brief clinical data of some of the most effective photosensitizers. The utility of the tumor-avid photosensitizers in developing multimodality agents (imaging and therapy) is also presented.199Pandey, S. K.; Gryshuk, A. L.; Sajjad, M.; Zheng, X.; Chen, Y.; Abouzeid, M. M.; Morgan, J.; Charamisinau, I.; Nabi, H. A.; Oseroff, A.; Pandey, R. K. Multimodality Agents for Tumor Imaging (Pet, Fluorescence) and Photodynamic Therapy. A Possible “See and Treat” Approach. J. Med. Chem. 2005, 48, 6286– 6295, DOI: 10.1021/jm050427m[ACS Full Text], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXpslWrsb0%253D&md5=65ad82b5d6a51f28ac4d0bf998f90e2eMultimodality Agents for Tumor Imaging (PET, Fluorescence) and Photodynamic Therapy. A Possible "See and Treat" ApproachPandey, Suresh K.; Gryshuk, Amy L.; Sajjad, Munawwar; Zheng, Xiang; Chen, Yihui; Abouzeid, Mohei M.; Morgan, Janet; Charamisinau, Ivan; Nabi, Hani A.; Oseroff, Allan; Pandey, Ravindra K.Journal of Medicinal Chemistry (2005), 48 (20), 6286-6295CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Me 3-(1'-m-iodobenzyloxyethyl)-3-devinylpyropheophorbide-a (2), obtained in a sequence of reactions from pyropheophorbide-a (a chlorophyll-a deriv.), was found to be a promising imaging agent and a photosensitizer for photodynamic therapy (PDT). The electrophillic arom. iodination of the corresponding trimethylstannyl intermediate with Na124I in the presence of an Iodogen bead afforded 124I-labeled photosensitizer 4 with >95% radioactive specificity. In addn. to drug-uptake, the light fluence and fluence rate that were used for the light treatment had a significant impact in long-term tumor cure. The iodo photosensitizer 2 (nonlabeled analog of 4) produced 100% tumor cure (5/5 mice were tumor free on day 60) at a dose of 1.5 μmol/kg and a light dose of 128 J/cm2, 14 mW/cm2 for 2.5 h (λmax 665 nm) at 24 h postinjection. The photosensitizer also showed promising tumor fluorescence and PET imaging ability. Our present work demonstrates the utility of the first 124I-labeled photosensitizer as a "multimodality agent", which could further be improved by using more tumor-avid and/or target-specific photosensitizers.200Edrei, R.; Gottfried, V.; van Lier, J. E.; Kimel, S. Sulfonated Phthalocyanines: Photophysical Properties, in Vitro Cell Uptake and Structure-Activity Relationships. J. Porphyrins Phthalocyanines 1998, 2, 191– 199, DOI: 10.1002/(SICI)1099-1409(199805/06)2:3<191::AID-JPP65>3.3.CO;2-W[Crossref], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXlsFOnsbw%253D&md5=415dfb6b9a0e96142f8df650beb9b79cSulfonated phthalocyanines: photophysical properties, in vitro cell uptake and structure-active relationshipsEdrei, R.; Gottfried, V.; Van Lier, J. E.; Kimel, S.Journal of Porphyrins and Phthalocyanines (1998), 2 (3), 191-199CODEN: JPPHFZ; ISSN:1088-4246. (John Wiley & Sons Ltd.)Aluminum phthalocyanines sulfonated to a different degree (AlPcSn) and consisting of various isomeric species were studied by spectroscopic techniques to det. their tendencies to form dimers and aggregates. These characteristics were compared with the cell-penetrating properties of the species, using the Ehrlich ascites mouse tumor cell line, to arrive at structure-activity relationships. AlPcSn prepns. consisting of the least no. of isomeric species exhibited the highest tendency to form dimers and aggregates, whereas the more complex prepns., consisting of many isomeric products, showed more consistent monomeric features in aq. environments. Uptake in cells was shown to correlate well with the overall hydrophobicity of the prepn. and inversely with its degree of aggregation in the extracellular environment. Among the purified, single isomeric AlPcSn the amphiphilic disulfonated AlPcS2a, enriched in positional isomers featuring sulfonate groups on adjacent phthalic subunits, showed the best membrane-penetrating properties. Even higher cell uptake was obsd. for the AlPcS2mix reflecting a combination of optimal lipophilicity and a low degree of aggregation. Similarly, in the case of AlPcS4, the pure isomeric compd. showed less cell uptake than the mixed isomeric prepn. of similar hydrophobicity, reflecting the higher degree of aggregation invoked by its sym. structure. Our data indicate that mixed sulfonated phthalocyanine prepns. may exert higher photodynamic efficacy in biol. applications as compared to the pure isomeric constituents.201Chan, W. M.; Lim, T. H.; Pece, A.; Silva, R.; Yoshimura, N. Verteporfin PDT for Non-Standard Indications-A Review of Current Literature. Graefe's Arch. Clin. Exp. Ophthalmol. 2010, 248, 613– 626, DOI: 10.1007/s00417-010-1307-z[Crossref], [PubMed], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjvFSnuro%253D&md5=1c222766382e77ff435921f559831d58Verteporfin PDT for non-standard indications-a review of current literatureChan, Wai Man; Lim, Tock-Han; Pece, Alfredo; Silva, Rufino; Yoshimura, NagahisaGraefe's Archive for Clinical and Experimental Ophthalmology (2010), 248 (5), 613-626CODEN: GACODL; ISSN:0721-832X. (Springer)A review. Background: Verteporfin photodynamic therapy (PDT) is approved for the treatment of predominantly classic subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD), as well as for subfoveal CNV due to pathol. myopia and ocular histoplasmosis syndrome. Verteporfin PDT addresses the underlying pathol. of ocular vascular disorders through its angio-occlusive mechanism of action, which reduces both visual acuity loss and the underlying leakage assocd. with lesions. Verteporfin PDT has also been assocd. with encouraging treatment outcomes in case studies involving patients with choroidal vascular disorders such as polypoidal choroidal vasculopathy, central serous chorioretinopathy, choroidal haemangioma, angioid streaks, and inflammatory CNV, i.e. conditions currently considered as non-std. indications of verteporfin PDT. In many studies, outcomes were better than expected based on the natural courses of each of these conditions. Although the anti-vascular endothelial growth factor (VEGF) therapies, ranibizumab and pegaptanib, have been approved for CNV due to AMD, their role in these other choroidal vascular disorders remains to be established. We summarize current literature that has documented the use of verteporfin PDT in these conditions. Conclusions: The complex pathogenesis of CNV provides a rationale for investigating combination approaches comprising verteporfin PDT and anti-VEGF therapies. Randomized controlled studies are warranted to confirm the preliminary results of verteporfin PDT as a monotherapy or in combination with anti-VEGF therapies in the treatment of a variety of choroidal vascular conditions.202Skupin-Mrugalska, P.; Piskorz, J.; Goslinski, T.; Mielcarek, J.; Konopka, K.; Düzgüneş, N. Current Status of Liposomal Porphyrinoid Photosensitizers. Drug Discovery Today 2013, 18, 776– 784, DOI: 10.1016/j.drudis.2013.04.003[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntV2gsr0%253D&md5=81bccd78bf2fe2cd0a959bd1606d9ca7Current status of liposomal porphyrinoid photosensitizersSkupin-Mrugalska, Paulina; Piskorz, Jaroslaw; Goslinski, Tomasz; Mielcarek, Jadwiga; Konopka, Krystyna; Duzgunes, NejatDrug Discovery Today (2013), 18 (15-16), 776-784CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. The complete eradication of various targets, such as infectious agents or cancer cells, while leaving healthy host cells untouched, is still a great challenge faced in the field of medicine. Photodynamic therapy (PDT) seems to be a promising approach for anticancer treatment, as well as to combat various dermatol. and ophthalmic diseases and microbial infections. The application of liposomes as delivery systems for porphyrinoids has helped overcome many drawbacks of conventional photosensitizers and facilitated the development of novel effective photosensitizers that can be encapsulated in liposomes. The development, preclin. studies and future directions for liposomal delivery of conventional and novel photosensitizers are reviewed.203Yuzhakova, D. V.; Lermontova, S. A.; Grigoryev, I. S.; Muravieva, M. S.; Gavrina, A. I.; Shirmanova, M. V.; Balalaeva, I. V.; Klapshina, L. G.; Zagaynova, E. V. In Vivo Multimodal Tumor Imaging and Photodynamic Therapy With Novel Theranostic Agents Based on the Porphyrazine Framework-Chelated Gadolinium (III) Cation. Biochim. Biophys. Acta, Gen. Subj. 2017, 1861, 3120– 3130, DOI: 10.1016/j.bbagen.2017.09.004[Crossref], [PubMed], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFOrt73I&md5=663fa67992c309e968412b630507401eIn vivo multimodal tumor imaging and photodynamic therapy with novel theranostic agents based on the porphyrazine framework-chelated gadolinium (III) cationYuzhakova, Diana V.; Lermontova, Svetlana A.; Grigoryev, Ilya S.; Muravieva, Maria S.; Gavrina, Alena I.; Shirmanova, Marina V.; Balalaeva, Irina V.; Klapshina, Larisa G.; Zagaynova, Elena V.Biochimica et Biophysica Acta, General Subjects (2017), 1861 (12), 3120-3130CODEN: BBGSB3; ISSN:0304-4165. (Elsevier B.V.)A promising strategy for cancer diagnosis and therapy is the development of an agent for multimodal imaging and treatment. In the present paper we report on two novel multifunctional agents prepd. on the porphyrazine pigment platform using a gadolinium (III) cation chelated by red-fluorescent tetrapyrrole macrocycles (GdPz1 and GdPz2). Spectral and magnetic properties of the compds. were analyzed. Monitoring of GdPz1 and GdPz2 accumulation in the murine colon carcinoma CT26 was performed in vivo using fluorescence imaging and MRI. The photobleaching of GdPz1 or GdPz2 and tumor growth rate after photodynamic therapy (PDT) were assessed. GdPz1 and GdPz2 demonstrated the selective accumulation in tumor that was indicated by higher fluorescence intensity in the tumor area in comparison with the normal tissues. The results of MRI in vivo showed that GdPz1 or GdPz2 provided significant contrast enhancement of the tumor in T1 MR images. PDT with GdPz2 resulted in ∼ 20% decrease in fluorescence intensity of the compd. and the inhibition of tumor growth. We assessed the efficiency of two innovative Gd(III) cation-porphyrazine chelates as bimodal MR and fluorescent probes and photosensitizers for PDT and showed their potentials for tumor diagnostics and treatment. Water-sol. structures simple in prepn. and administration into the body represent special interest for theranostics of tumors. Novel porphyrazine macrocycles chelating a central gadolinium cation demonstrated a good prospect as effective multimodal agents, representing a new approach to MRI and fluorescence imaging guided PDT.204Lim, E. K.; Kim, T.; Paik, S.; Haam, S.; Huh, Y. M.; Lee, K. Nanomaterials for Theranostics: Recent Advances and Future Challenges. Chem. Rev. 2015, 115, 327– 394, DOI: 10.1021/cr300213b[ACS Full Text], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFOhtrrE&md5=09851ca615fa19e7bed7f065a8bef3f4Nanomaterials for Theranostics: Recent Advances and Future ChallengesLim, Eun-Kyung; Kim, Taekhoon; Paik, Soonmyung; Haam, Seungjoo; Huh, Yong-Min; Lee, KwangyeolChemical Reviews (Washington, DC, United States) (2015), 115 (1), 327-394CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)There is no expanded citation for this reference.205Louie, A. Multimodality Imaging Probes: Design and Challenges. Chem. Rev. 2010, 110, 3146– 3195, DOI: 10.1021/cr9003538[ACS Full Text], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtFOqsr4%253D&md5=ae6a5921dd5db0eaae335ac40a12141aMultimodality Imaging Probes: Design and ChallengesLouie, AngeliqueChemical Reviews (Washington, DC, United States) (2010), 110 (5), 3146-3195CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review.206Edwards, W. B.; Xu, B.; Akers, W.; Cheney, P. P.; Liang, K.; Rogers, B. E.; Anderson, C. J.; Achilefu, S. Agonist - Antagonist Dilemma in Molecular Imaging: Evaluation of a Monomolecular Multimodal Imaging Agent for the Somatostatin Receptor. Bioconjugate Chem. 2008, 19, 192– 200, DOI: 10.1021/bc700291m[ACS Full Text], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlejsbnN&md5=e8df35629b7e2d69c8d1a896b0122557Agonist-Antagonist Dilemma in Molecular Imaging: Evaluation of a Monomolecular Multimodal Imaging Agent for the Somatostatin ReceptorEdwards, W. Barry; Xu, Baogang; Akers, Walter; Cheney, Philip P.; Liang, Kexian; Rogers, Buck E.; Anderson, Carolyn J.; Achilefu, SamuelBioconjugate Chemistry (2008), 19 (1), 192-200CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)The combination of different imaging modalities, each providing information according to its strengths, can be a powerful method for diagnosing diseases. We have synthesized a monomol. multimodal imaging agent (MOMIA), LS172, contg. a subtype-2 somatostatin receptor (SSTr2)-avid peptide (Y3-octreotate or Y3-TATE), a radiometal chelating group (DOTA) and a near-IR (NIR) fluorescent dye (cypate). In addn. to optical methods, radiolabeling LS172 with 64Cu and 177Lu provides a strategy for in vitro evaluation or in vivo multimodal imaging by positron emission tomog. (PET) and single photon emission computed tomog. (SPECT), resp. Detn. of the binding affinity of LS172, natCu- and natLu-LS172 in SSTr2-transfected A427 cells (A427-7) showed that they all displayed high binding affinity toward SSTr2 with Ki values of 0.234 nM, 11.5 nM, and 2.15 nM resp. In contrast to cypate-labeled Y3-TATE (cytate), fluorescence microscopy showed that LS172 and natCu-LS172 accumulate modestly in A427-7 cells by SSTr2-mediated endocytosis, in spite of their relatively high binding affinity. In vivo, the biodistribution of the SSTr2 receptor specific 64Cu- and 177Lu-LS172 in AR42J tumor-bearing rats exhibited low (≤1% ID/g) accumulation in tumor tissue. Clearance from circulation was predominantly hepatobiliary (>90% ID/liver). Both optical and radionuclear biodistribution studies showed a similar in vivo distribution profile. Surprisingly, the strong binding of LS172 to SSTr2 did not translate into high SSTr2-mediated endocytosis in cells or uptake in tumor in vivo. Considering that LS172 is a putative antagonist, the poor accumulation of the labeled MOMIAs in SSTr2 pos. tumor tissue supports the paradigm that agonists with their concomitant internalization favors appreciable target tissue accumulation of receptor-specific ligands.207Walia, S.; Acharya, A. Silica Micro/Nanospheres for Theranostics: From Bimodal MRI and Fluorescent Imaging Probes to Cancer Therapy. Beilstein. Beilstein J. Nanotechnol. 2015, 6, 546– 558, DOI: 10.3762/bjnano.6.57[Crossref], [PubMed], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXls1Kks74%253D&md5=5a33b284c15ad7e9430817ca39abf9eeSilica micro/nanospheres for theranostics: from bimodal MRI and fluorescent imaging probes to cancer therapyWalia, Shanka; Acharya, AmitabhaBeilstein Journal of Nanotechnology (2015), 6 (), 546-558CODEN: BJNEAH; ISSN:2190-4286. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)Nano-theranostics offer remarkable potential for future biomedical technol. with simultaneous applications for diagnosis and therapy of disease sites. Through smart and careful chem. modifications of the nanoparticle surface, these can be converted to multifunctional tiny objects which in turn can be used as vehicle for delivering multimodal imaging agents and therapeutic material to specific target sites in vivo. In this sense, bimodal imaging probes that simultaneously enable magnetic resonance imaging and fluorescence imaging have gained tremendous attention because disease sites can be characterized quick and precisely through synergistic multimodal imaging. But such hybrid nanocomposite materials have limitations such as low chem. stability (magnetic component) and harsh cytotoxic effects (fluorescent component) and, hence, require a biocompatible protecting agent. Silica micro/nanospheres have shown promise as protecting agent due to the high stability and low toxicity. This review will cover a full description of MRI-active and fluorescent multifunctional silica micro/nanospheres including the design of the probe, different characterization methods and their application in imaging and treatment in cancer.208Pandey, S. K.; Kaur, J.; Easwaramoorthy, B.; Shah, A.; Coleman, R.; Mukherjee, J. Multimodality Imaging Probe for Positron Emission Tomography and Fluorescence Imaging Studies. Mol. Imaging 2014, 13, 1– 7, DOI: 10.2310/7290.2014.00005[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cjisFamsg%253D%253D&md5=64af2b6bc545e1b689b670f71e5f7affMultimodality imaging probe for positron emission tomography and fluorescence imaging studiesPandey Suresh K; Kaur Jasmeet; Easwaramoorthy Balu; Shah Ankur; Coleman Robert; Mukherjee JogeshwarMolecular imaging (2014), 13 (), 1-7 ISSN:.Our goal is to develop multimodality imaging agents for use in cell tracking studies by positron emission tomography (PET) and optical imaging (OI). For this purpose, bovine serum albumin (BSA) was complexed with biotin (histologic studies), 5(6)-carboxyfluorescein, succinimidyl ester (FAM SE) (OI studies), and diethylenetriamine pentaacetic acid (DTPA) for chelating gallium 68 (PET studies). For synthesis of BSA-biotin-FAM-DTPA, BSA was coupled to (+)-biotin N-hydroxysuccinimide ester (biotin-NHSI). BSA-biotin was treated with DTPA-anhydride and biotin-BSA-DTPA was reacted with FAM. The biotin-BSA-DTPA-FAM was reacted with gallium chloride 3 to 5 mCi eluted from the generator using 0.1 N HCl and was passed through basic resin (AG 11 A8) and 150 μCi (100 μL, pH 7-8) was incubated with 0.1 mg of FAM conjugate (100 μL) at room temperature for 15 minutes to give 68Ga-BSA-biotin-DTPA-FAM. A shaved C57 black mouse was injected with FAM conjugate (50 μL) at one flank and FAM-68Ga (50 μL, 30 μCi) at the other. Immediately after injection, the mouse was placed in a fluorescence imaging system (Kodak In-Vivo F, Bruker Biospin Co., Woodbridge, CT) and imaged (λex: 465 nm, λem: 535 nm, time: 8 seconds, Xenon Light Source, Kodak). The same mouse was then placed under an Inveon microPET scanner (Siemens Medical Solutions, Knoxville, TN) injected (intravenously) with 25 μCi of 18F and after a half-hour (to allow sufficient bone uptake) was imaged for 30 minutes. Molecular weight determined using matrix-associated laser desorption ionization (MALDI) for the BSA sample was 66,485 Da and for biotin-BSA was 67,116 Da, indicating two biotin moieties per BSA molecule; for biotin-BSA-DTPA was 81,584 Da, indicating an average of 30 DTPA moieties per BSA molecule; and for FAM conjugate was 82,383 Da, indicating an average of 1.7 fluorescent moieties per BSA molecule. Fluorescence imaging clearly showed localization of FAM conjugate and FAM-68Ga at respective flanks of the mouse, whereas only a hot spot at the expected flank (FAM-68Ga injection site) was observed in microPET imaging. Our results suggest that BSA-biotin-DTPA-FAM may function as a multiprobe for PET and fluorescence imaging. Experiments are currently in progress to demonstrate cell tracking using both optical and nuclear imaging.209Wolfbeis, O. S. An Overview of Nanoparticles Commonly Used in Fluorescent Bioimaging. Chem. Soc. Rev. 2015, 44, 4743– 4768, DOI: 10.1039/C4CS00392F[Crossref], [PubMed], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVGisrs%253D&md5=c657579740ee90d89e452ef3e6169f78An overview of nanoparticles commonly used in fluorescent bioimagingWolfbeis, Otto S.Chemical Society Reviews (2015), 44 (14), 4743-4768CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)This article gives an overview of the various kinds of nanoparticles (NPs) that are widely used for purposes of fluorescent imaging, mainly of cells and tissues. Following an introduction and a discussion of merits of fluorescent NPs compared to mol. fluorophores, labels and probes, the article assesses the kinds and specific features of nanomaterials often used in bioimaging. These include fluorescently doped silicas and sol-gels, hydrophilic polymers (hydrogels), hydrophobic org. polymers, semiconducting polymer dots, quantum dots, carbon dots, other carbonaceous nanomaterials, upconversion NPs, noble metal NPs (mainly gold and silver), various other nanomaterials, and dendrimers. Another section covers coatings and methods for surface modification of NPs. Specific examples on the use of nanoparticles in (a) plain fluorescence imaging of cells, (b) targeted imaging, (c) imaging of chem. species, and (d) imaging of temp. are given next. A final section covers aspects of multimodal imaging (such as fluorescence/nmr), imaging combined with drug and gene delivery, or imaging combined with therapy or diagnosis. The electronic supplementary information (ESI) gives specific examples for materials and methods used in imaging, sensing, multimodal imaging and theranostics such as imaging combined with drug delivery or photodynamic therapy. The article contains 273 refs. in the main part, and 157 refs. in the ESI.210Thomas, R.; Park, I. K.; Jeong, Y. Y. Magnetic Iron Oxide Nanoparticles for Multimodal Imaging and Therapy of Cancer. Int. J. Mol. Sci. 2013, 14, 15910– 15930, DOI: 10.3390/ijms140815910[Crossref], [PubMed], [CAS], Google Scholar210https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlWqur7P&md5=7bbea4aca21f1056f9fe7dd35a944d87Magnetic iron oxide nanoparticles for multimodal imaging and therapy of cancerThomas, Reju; Park, In-Kyu; Jeong, Yong YeonInternational Journal of Molecular Sciences (2013), 14 (8), 15910-15930, 21 pp.CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. Superparamagnetic iron oxide nanoparticles (SPION) have emerged as an MRI contrast agent for tumor imaging due to their efficacy and safety. Their utility has been proven in clin. applications with a series of marketed SPION-based contrast agents. Extensive research has been performed to study various strategies that could improve SPION by tailoring the surface chem. and by applying addnl. therapeutic functionality. Research into the dual-modal contrast uses of SPION has developed because these applications can save time and effort by reducing the no. of imaging sessions. In addn. to multimodal strategies, efforts have been made to develop multifunctional nanoparticles that carry both diagnostic and therapeutic cargos specifically for cancer. This review provides an overview of recent advances in multimodality imaging agents and focuses on iron oxide based nanoparticles and their theranostic applications for cancer. Furthermore, we discuss the physiochem. properties and compare different synthesis methods of SPION for the development of multimodal contrast agents.211Vanderesse, D. B. Innovations of Photodynamic Therapy for Brain Tumors: Potential of Multifunctional Nanoparticles. J. Carcinog. Mutagen. 2014, 8, 8, DOI: 10.4172/2157-2518.S8-001212Glasgow, M. D. K.; Chougule, M. B. Recent Developments in Active Tumor Targeted Multifunctional Nanoparticles for Combination Chemotherapy in Cancer Treatment and Imaging. J. Biomed. Nanotechnol. 2015, 11, 1859– 1898, DOI: 10.1166/jbn.2015.2145[Crossref], [PubMed], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XlsVeisA%253D%253D&md5=f662c426459c7228c97c2f924f092916Recent developments in active tumor targeted multifunctional nanoparticles for combination chemotherapy in cancer treatment and imagingGlasgow, Micah D. K.; Chougule, Mahavir B.Journal of Biomedical Nanotechnology (2015), 11 (11), 1859-1898CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)Nanotechnol. and combination therapy are two major fields that show great promise in the treatment of cancer. The delivery of drugs via nanoparticles helps to improve drug's therapeutic effectiveness while reducing adverse side effects assocd. with high dosage by improving their pharmacokinetics. Taking advantage of mol. markers over-expressing on tumor tissues compared to normal cells, an "active" mol. marker targeted approach would be-beneficial for cancer therapy. These actively targeted nanoparticles would increase drug concn. at the tumor site, improving efficacy while further reducing chemo-resistance. The multidisciplinary approach may help to improve the overall efficacy in cancer therapy. This review article summarizes recent developments of targeted multifunctional nanoparticles in the delivery of various drugs for a combinational chemotherapy approach to cancer treatment and imaging.213Nafiujjaman, M.; Revuri, V.; Nurunnabi, M.; Jae Cho, K.; Lee, Y. K. Photosensitizer Conjugated Iron Oxide Nanoparticles for Simultaneous in Vitro Magneto-Fluorescent Imaging Guided Photodynamic Therapy. Chem. Commun. 2015, 51, 5687– 5690, DOI: 10.1039/C4CC10444G[Crossref], [PubMed], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXislKis7w%253D&md5=11eddb290b15e58a58d1674da5065beePhotosensitizer conjugated iron oxide nanoparticles for simultaneous in vitro magneto-fluorescent imaging guided photodynamic therapyNafiujjaman, Md; Revuri, Vishnu; Nurunnabi, Md; Jae Cho, Kwang; Lee, Yong-kyuChemical Communications (Cambridge, United Kingdom) (2015), 51 (26), 5687-5690CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)In this study, photosensitizer conjugated iron oxide nanoparticles were strategically designed and prepd. for simultaneous PDT and dual-mode fluorescence/MR imaging. The MRI contrast agent Fe3O4 was modified by APTES to functionalize the surface and further to link with heparin-pheophorbide-A conjugates.214Wang, D.; Fei, B.; Halig, L. V.; Qin, X.; Hu, Z.; Xu, H.; Wang, Y. A.; Chen, Z.; Kim, S.; Shin, D. M.; Chen, Z. Targeted Iron-Oxide Nanoparticle for Photodynamic Therapy and Imaging of Head and Neck Cancer. ACS Nano 2014, 8, 6620– 6632, DOI: 10.1021/nn501652j[ACS Full Text], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXps1Wjtbk%253D&md5=0aab744b29a213835df939cd81cfd9dcTargeted Iron-Oxide Nanoparticle for Photodynamic Therapy and Imaging of Head and Neck CancerWang, Dongsheng; Fei, Baowei; Halig, Luma V.; Qin, Xulei; Hu, Zhongliang; Xu, Hong; Wang, Yongqiang Andrew; Chen, Zhengjia; Kim, Sungjin; Shin, Dong M.; Chen, ZhuoACS Nano (2014), 8 (7), 6620-6632CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Photodynamic therapy (PDT) is a highly specific anticancer treatment modality for various cancers, particularly for recurrent cancers that no longer respond to conventional anticancer therapies. PDT has been under development for decades, but light-assocd. toxicity limits its clin. applications. To reduce the toxicity of PDT, we recently developed a targeted nanoparticle (NP) platform that combines a second-generation PDT drug, Pc 4, with a cancer targeting ligand, and iron oxide (IO) NPs. Carboxyl functionalized IO NPs were first conjugated with a fibronectin-mimetic peptide (Fmp), which binds integrin β1. Then the PDT drug Pc 4 was successfully encapsulated into the ligand-conjugated IO NPs to generate Fmp-IO-Pc 4. Our study indicated that both nontargeted IO-Pc 4 and targeted Fmp-IO-Pc 4 NPs accumulated in xenograft tumors with higher concns. than nonformulated Pc 4. As expected, both IO-Pc 4 and Fmp-IO-Pc 4 reduced the size of HNSCC xenograft tumors more effectively than free Pc 4. Using a 10-fold lower dose of Pc 4 than that reported in the literature, the targeted Fmp-IO-Pc 4 NPs demonstrated significantly greater inhibition of tumor growth than nontargeted IO-Pc 4 NPs. These results suggest that the delivery of a PDT agent Pc 4 by IO NPs can enhance treatment efficacy and reduce PDT drug dose. The targeted IO-Pc 4 NPs have great potential to serve as both a magnetic resonance imaging (MRI) agent and PDT drug in the clinic.215Luo, J.; Chen, L. F.; Hu, P.; Chen, Z. N. Tetranuclear Gadolinium(III) Porphyrin Complex as a Theranostic Agent for Multimodal Imaging and Photodynamic Therapy. Inorg. Chem. 2014, 53, 4184– 4191, DOI: 10.1021/ic500238s[ACS Full Text], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltlyks7o%253D&md5=02316e87bcf59cae7357222293e43ccfTetranuclear Gadolinium(III) Porphyrin Complex as a Theranostic Agent for Multimodal Imaging and Photodynamic TherapyLuo, Jian; Chen, Li-Feng; Hu, Ping; Chen, Zhong-NingInorganic Chemistry (2014), 53 (8), 4184-4191CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)We describe herein the elaborate design of a Gd(III)-porphyrin complex as a theranostic agent for multimodal imaging and photodynamic therapy. Far-red-emitting (665 nm) and high relaxivity (14.1 mM-1 s-1) with 107% increase upon binding to HSA (human serum albumin) (29.2 mM-1 s-1) together with efficiently generating singlet oxygen upon exposure to far-red light irradn. at 650 ± 20 nm demonstrate that this Gd(III)-porphyrin complex with four Gd(III)-DTTA units bound to tetraphenylporphyrin acts as a potentially theranostic agent with excellent performance for magnetic resonance imaging, optical imaging, and photodynamic therapy.216Spernyak, J. A.; White, W. H.; Ethirajan, M.; Patel, N. J.; Goswami, L.; Chen, Y.; Turowski, S.; Missert, J. R.; Batt, C.; Mazurchuk, R.; Pandey, R. K. Hexylether Derivative of Pyropheophorbide-a (HPPH) on Conjugating with 3 Gadolinium(III) Aminobenzyldiethylenetriaminepentaacetic Acid Shows Potential for In Vivo Tumor Imaging (MR, Fluorescence) and Photodynamic Therapy. Bioconjugate Chem. 2010, 21, 828– 835, DOI: 10.1021/bc9005317[ACS Full Text], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXksF2lsL0%253D&md5=8a8ac3bdad4a8fccb17ee993184d3e2aHexylether Derivative of Pyropheophorbide-a (HPPH) on Conjugating with 3Gadolinium(III) Aminobenzyldiethylenetriaminepentaacetic Acid Shows Potential for in Vivo Tumor Imaging (MR, Fluorescence) and Photodynamic TherapySpernyak, Joseph A.; White, William H., III; Ethirajan, Manivannan; Patel, Nayan J.; Goswami, Lalit; Chen, Yihui; Turowski, Steven; Missert, Joseph R.; Batt, Carrie; Mazurchuk, Richard; Pandey, Ravindra K.Bioconjugate Chemistry (2010), 21 (5), 828-835CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Conjugates of 3-(1'-hexyloxyethyl)-3-devinyl pyropheophorbide-a (HPPH) with multiple Gd(III)aminobenzyl diethylenetriamine pentacetic acid (ADTPA) moieties were evaluated for tumor imaging and photodynamic therapy (PDT). In vivo studies performed in both mice and rat tumor models resulted in a significant MR signal enhancement of tumors relative to surrounding tissues at 24 h postinjection. The water-sol. (pH: 7.4) HPPH-3Gd(III) ADTPA conjugate demonstrated high potential for tumor imaging by MR and fluorescence. This agent also produced long-term tumor cures via PDT. An in vivo biodistribution study with the corresponding 14C-analog also showed significant tumor uptake 24 h postinjection. Toxicol. evaluations of HPHH-3Gd(III)ADTPA administered at and above imaging/therapeutic doses did not show any evidence of organ toxicity. Our present study illustrates a novel approach for the development of water-sol. "multifunctional agents", demonstrating efficacy for tumor imaging (MR and fluorescence) and phototherapy.217An, F. F.; Chan, M.; Kommidi, H.; Ting, R. Dual PET and Near-Infrared Fluorescence Imaging Probes as Tools for Imaging in Oncology. AJR, Am. J. Roentgenol. 2016, 207, 266– 273, DOI: 10.2214/AJR.16.16181[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s%252FjtFGlsw%253D%253D&md5=cb5e99f9ce1603ec22a002715dfb3ca0Dual PET and Near-Infrared Fluorescence Imaging Probes as Tools for Imaging in OncologyAn Fei-Fei; Chan Mark; Kommidi Harikrishna; Ting RichardAJR. American journal of roentgenology (2016), 207 (2), 266-73 ISSN:.OBJECTIVE: The purpose of this article is to summarize advances in PET fluorescence resolution, agent design, and preclinical imaging that make a growing case for clinical PET fluorescence imaging. CONCLUSION: Existing SPECT, PET, fluorescence, and MRI contrast imaging techniques are already deeply integrated into the management of cancer, from initial diagnosis to the observation and management of metastases. Combined positron-emitting fluorescent contrast agents can convey new or substantial benefits that improve on these proven clinical contrast agents.218Seibold, U.; Wängler, B.; Schirrmacher, R.; Wängler, C. Bimodal Imaging Probes for Combined PET and OI: Recent Developments and Future Directions for Hybrid Agent Development. BioMed Res. Int. 2014, 16, 1, DOI: 10.1155/2014/153741219Nguyen, Q. T.; Tsien, R. Y. Fluorescence-Guided Surgery with Live Molecular Navigation-A New Cutting Edge. Nat. Rev. Cancer 2013, 13, 653– 662, DOI: 10.1038/nrc3566[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1emtrnL&md5=3e2d4d555e5d0cce02178d800a8a3e93Fluorescence-guided surgery with live molecular navigation - a new cutting edgeNguyen, Quyen T.; Tsien, Roger Y.Nature Reviews Cancer (2013), 13 (9), 653-662CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. A glowing new era in cancer surgery may be dawning. Using fluorescently labeled markers, surgical mol. navigation means that tumors and nerves can be displayed in real time intra-operatively in contrasting pseudocolors, which allows more complete tumor resection while preserving important structures. These advances can potentially cause a paradigm shift in cancer surgery, improving patient outcome and decreasing overall health-care costs.220Ghosh, S. C.; Azhdarinia, A. Advances in the Development of Multimodal Imaging Agents for Nuclear/Near-Infrared Fluorescence Imaging. Curr. Med. Chem. 2015, 22, 3390– 3404, DOI: 10.2174/0929867322666150904111214[Crossref], [PubMed], [CAS], Google Scholar220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Ont7nN&md5=3db771838cedeb590f57ddfcdd91b4b6Advances in the Development of Multimodal Imaging Agents for Nuclear/Near-infrared Fluorescence ImagingGhosh, S. C.; Azhdarinia, A.Current Medicinal Chemistry (2015), 22 (29), 3390-3404CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)Multimodal imaging agents were first introduced a decade ago and consist of a targeting moiety that is dual-labeled with radioactive and fluorescent contrast. These compds. allow whole-body and intraoperative imaging to be performed through administration of a single agent and provide complementary diagnostic information that can be used to guide tumor resection. Since their initial evaluation, interest in dual-labeled agents has continued to grow and their design has subsequently evolved alongside the development of novel chelating agents, improved fluorophores, and highly selective coupling techniques for bioconjugate formation. In this review, will discuss how changes in the labeling components and schemes for multimodal agent development have impacted imaging performance and will focus on antibody- and peptide-based agents as models for dual labeling. We will also describe the growing role of modular dual labeling strategies as well as direct labeling methods using radiohalogens.221Zeng, C.; Shang, W.; Wang, K.; Chi, C.; Jia, X.; Fang, C.; Yang, D.; Ye, J.; Fang, C.; Tian, J. Intraoperative Identification of Liver Cancer Microfoci Using a Targeted Near-Infrared Fluorescent Probe for Imaging-Guided Surgery. Sci. Rep. 2016, 6, 21959, DOI: 10.1038/srep21959[Crossref], [PubMed], [CAS], Google Scholar221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjsFegur4%253D&md5=aed0aadd9c9234d51578d5e06051aeccIntraoperative Identification of Liver Cancer Microfoci Using a Targeted Near-Infrared Fluorescent Probe for Imaging-Guided SurgeryZeng, Chaoting; Shang, Wenting; Wang, Kun; Chi, Chongwei; Jia, Xiaohua; Fang, Cheng; Yang, Du; Ye, Jinzuo; Fang, Chihua; Tian, JieScientific Reports (2016), 6 (), 21959CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Difficulties in the highly sensitive detection of tumor microfoci represent a crit. obstacle toward improved surgical intervention in liver cancer. Conventional preoperative imaging methods and surgeons' subjective experience are limited by their inability to effectively detect tumor lesions measuring less than 2 mm; however, intraoperative fluorescence mol. imaging may overcome this limitation. Here, we synthesized an arginine-glycine-aspartic acid (RGD)-conjugated mesoporous silica nanoparticle (MSN) highly loaded with indocyanine green (ICG) dye that could accurately delineate liver cancer margins and provide excellent tumor-to-normal tissue contrast intraoperatively. The increased ICG loading capacity and tumor specificity enabled the identification of residual microtumors and satellite lesions measuring less than 1 mm in living mice. Histol. anal. validated the sensitivity and accuracy of this approach. We believe this technique utilizing a new fluorescent nanoprobe with intraoperative optical imaging may offer a more sensitive and accurate method for liver cancer resection guidance, resulting in better surgical outcomes.222Li, X.; Zhang, X.-N.; Li, X.-D.; Chang, J.; Li, X.; Zhang, X.-N.; Li, X.-D.; Chang, J. Multimodality Imaging in Nanomedicine and Nanotheranostics. Cancer Biol. Med. 2016, 13, 339– 348, DOI: 10.20892/j.issn.2095-3941.2016.0055[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvVWhs74%253D&md5=ab9da73bad6529f9178f0b005e756011Multimodality imaging in nanomedicine and nanotheranosticsLi, Xue; Zhang, Xue-Ning; Li, Xiao-Dong; Chang, JinCancer Biology & Medicine (2016), 13 (3Spec.Iss.), 339-348CODEN: CBMADQ ISSN:. (Tianjin Medical University Cancer Institute and Hospital)Accurate diagnosis of tumors needs much detailed information. However, available single imaging modality cannot provide complete or comprehensive data. Nanomedicine is the application of nanotechnol. to medicine, and multimodality imaging based on nanoparticles has been receiving extensive attention. This new hybrid imaging technol. could provide complementary information from different imaging modalities using only a single injection of contrast agent. In this review, we introduce recent developments in multifunctional nanoparticles and their biomedical applications to multimodal imaging and theragnosis as nanomedicine. Most of the reviewed studies are based on the intrinsic properties of nanoparticles and their application in clin. imaging technol. The imaging techniques include positron emission tomog., single-photon emission computed tomog., computerized tomog., magnetic resonance imaging, optical imaging, and ultrasound imaging.223Durnev, A. D. Toxicology of Nanoparticles. Bull. Bull. Exp. Biol. Med. 2008, 145, 72– 74, DOI: 10.1007/s10517-008-0005-x[Crossref], [PubMed], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cjlvVyltQ%253D%253D&md5=9c2575bd11ba75ab9dcc34002068e548Toxicology of nanoparticlesDurnev A DBulletin of experimental biology and medicine (2008), 145 (1), 72-4 ISSN:0007-4888.The paper considers the basic directions in fundamental and applied studies of the toxic effects of nanoparticles. Of particular importance is the study aimed at evaluation of the dependence of these effects on the shape, size, initial material, surface area, electric charge, and other physicochemical structural peculiarities, as well as on the dosage, mode of application, concentration in the target organ, and duration of action. The differences are stressed in the realization of general toxicity and genotoxicity of nanoparticles and chemical agents. The importance of the development of new methods of preclinical assessment of the safety of therapeutic nanoderivatives is emphasized.224Liu, Z.; Kiessling, F.; Gätjens, J. Advanced Nanomaterials in Multimodal Imaging: Design, Functionalization, and Biomedical Applications. J. Nanomater. 2010, 2010, 1, DOI: 10.1155/2010/894303225Head, H. W.; Dodd, G. D.; Bao, A.; Soundararajan, A.; Garcia-Rojas, X.; Prihoda, T. J.; McManus, L. M.; Goins, B. A.; Santoyo, C. A.; Phillips, W. T. Combination Radiofrequency Ablation and Intravenous Radiolabeled Liposomal Doxorubicin: Imaging and Quantification of Increased Drug Delivery to Tumors. Radiology 2010, 255, 405– 414, DOI: 10.1148/radiol.10090714[Crossref], [PubMed], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c3otlamtQ%253D%253D&md5=347ca11fd7fdf42aa8e5d1a19eaa3b2eCombination radiofrequency ablation and intravenous radiolabeled liposomal Doxorubicin: imaging and quantification of increased drug delivery to tumorsHead Hayden W; Dodd Gerald D 3rd; Bao Ande; Soundararajan Anuradha; Garcia-Rojas Xavier; Prihoda Thomas J; McManus Linda M; Goins Beth A; Santoyo Cristina A; Phillips William TRadiology (2010), 255 (2), 405-14 ISSN:.PURPOSE: To identify, with noninvasive imaging, the zone of radiopharmaceutical uptake after combination therapy with radiofrequency (RF) ablation and intravenous administration of technetium 99m ((99m)Tc) liposomal doxorubicin in a small-animal tumor model, and to quantify and correlate the uptake by using imaging and tissue counting of intratumoral doxorubicin accumulation. MATERIALS AND METHODS: This study was approved by the animal care committee. Two phases of animal experiments were performed. In the first experiment, a single human head-and-neck squamous cell carcinoma tumor was grown in each of 10 male nude rats. Seven of these animals were treated with intravenous (99m)Tc-liposomal doxorubicin followed by RF tumor ablation at a mean temperature of 70 degrees C + or - 2 for 5 minutes, and three were treated with intravenous (99m)Tc-liposomal doxorubicin only. Combination single photon emission computed tomography-computed tomography (SPECT/CT) was performed at 15 minutes, 4 hours, and 20 hours after therapy. In the second experiment, two tumors each were grown in 11 rats, but only one of the tumors was ablated after intravenous administration of (99m)Tc-liposomal doxorubicin. SPECT/CT and planar scintigraphy were performed at the same posttreatment intervals applied in the first experiment, with additional planar imaging performed at 44 hours. After imaging, tissue counting in the excised tumors was performed. Radiotracer uptake, as determined with imaging and tissue counting, was quantified and compared. In a subset of three animals, intratumoral doxorubicin accumulation was determined with fluorimetry and correlated with the imaging and tissue-counting data. RESULTS: At both SPECT/CT and planar scintigraphy, increased uptake of (99m)Tc-liposomal doxorubicin was visibly apparent in the ablated tumors. Results of quantitative analysis with both imaging and tissue counting confirmed significantly greater uptake in the RF ablation-treated tumors (P < .001). Intratumoral doxorubicin accumulation correlated closely with imaging (r = 0.9185-0.9871) and tissue-counting (r = 0.995) results. CONCLUSION: Study results show that increased delivery of intravenous liposomal doxorubicin to tumors combined with RF ablation can be depicted and quantified with noninvasive imaging.226Ljungkvist, A. S. E.; Bussink, J.; Kaanders, J. H. A. M.; van der Kogel, A. J. Dynamics of Tumor Hypoxia Measured with Bioreductive Hypoxic Cell Markers. Radiat. Res. 2007, 167, 127– 145, DOI: 10.1667/RR0719.1[Crossref], [PubMed], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlOhs78%253D&md5=6651faff795bb0e8420f2310e9fc151cDynamics of tumor hypoxia measured with bioreductive hypoxic cell markersLjungkvist, Anna S. E.; Bussink, Johan; Kaanders, Johannes H. A. M.; van der Kogel, Albert J.Radiation Research (2007), 167 (2), 127-145CODEN: RAREAE; ISSN:0033-7587. (Radiation Research Society)A review. Hypoxic cells are common in tumors and contribute to malignant progression, distant metastasis and resistance to radiotherapy. It is well known that tumors are heterogeneous with respect to the levels and duration of hypoxia. Several strategies, including high-oxygen-content gas breathing, radiosensitizers and hypoxic cytotoxins, have been developed to overcome hypoxia-mediated radioresistance. However, with these strategies, an increased tumor control rate is often accompanied by more severe side effects. Consequently, development of assays for prediction of tumor response and early monitoring of treatment responses could reduce both over- and undertreatment, thereby avoiding unnecessary side effects. The purpose of this review is to discuss different assays for measurement of hypoxia that can be used to detect changes in oxygen tension. The main focus is on exogenous bioreductive hypoxia markers (2-nitroimidazoles) such as pimonidazole, CCI-103F, EF5 and F-misonidazole. These are specifically reduced and bind to macromols. in viable hypoxic cells. A no. of these bioreductive drugs are approved for clin. use and can be detected with methods ranging from noninvasive PET imaging (low resoln.) to microscopic imaging of tumor sections (high resoln.). If the latter are stained for multiple markers, hypoxia can be analyzed in relation to different microenvironmental parameters such as vasculature, proliferation and endogenous hypoxia-related markers, for instance HIF1α and CA-IX. In addn., temporal and spatial changes in hypoxia can be analyzed by consecutive injection of two different hypoxia markers. Therefore, bioreductive exogenous hypoxia markers are promising as tools for development of predictive assays or as tools for early treatment monitoring and validation of potential endogenous hypoxia markers.227Vaupel, P.; Mayer, A. Hypoxia in Cancer: Significance and Impact on Clinical Outcome. Cancer Metastasis Rev. 2007, 26, 225– 239, DOI: 10.1007/s10555-007-9055-1[Crossref], [PubMed], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXotFWrtLo%253D&md5=63da460ae8b28b0fd6e5b69b10e7894dHypoxia in cancer: significance and impact on clinical outcomeVaupel, Peter; Mayer, ArnulfCancer and Metastasis Reviews (2007), 26 (2), 225-239CODEN: CMRED4; ISSN:0167-7659. (Springer)A review. Hypoxia, a characteristic feature of locally advanced solid tumors, has emerged as a pivotal factor of the tumor (patho-)physiome since it can promote tumor progression and resistance to therapy. Hypoxia represents a "Janus face" in tumor biol. because (a) it is assocd. with restrained proliferation, differentiation, necrosis or apoptosis, and (b) it can also lead to the development of an aggressive phenotype. Independent of std. prognostic factors, such as tumor stage and nodal status, hypoxia has been suggested as an adverse prognostic factor for patient outcome. Studies of tumor hypoxia involving the direct assessment of the oxygenation status have suggested worse disease-free survival for patients with hypoxic cervical cancers or soft tissue sarcomas. In head & neck cancers the studies suggest that hypoxia is prognostic for survival and local control. Tech. limitations of the direct O2 sensing technique have prompted the use of surrogate markers for tumor hypoxia, such as hypoxia-related endogenous proteins (e.g., HIF-1α, GLUT-1, CA IX) or exogenous bioreductive drugs. In many-albeit not in all-studies endogenous markers showed prognostic significance for patient outcome. The prognostic relevance of exogenous markers, however, appears to be limited. Noninvasive assessment of hypoxia using imaging techniques can be achieved with PET or SPECT detection of radiolabeled tracers or with MRI techniques (e.g., BOLD). Clin. experience with these methods regarding patient prognosis is so far only limited. In the clin. studies performed up until now, the lack of standardized treatment protocols, inconsistencies of the endpoints characterizing the oxygenation status and methodol. differences (e.g., different immunohistochem. staining procedures) may compromise the power of the prognostic parameter used.228Brown, J. M. Tumor Hypoxia, Drug Resistance, and Metastases. J. Natl. Cancer Inst. 1990, 82, 338– 339, DOI: 10.1093/jnci/82.5.338[Crossref], [PubMed], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3c7ls1eqtA%253D%253D&md5=359a883d682549b19347e1e243ae9abaTumor hypoxia, drug resistance, and metastasesBrown J MJournal of the National Cancer Institute (1990), 82 (5), 338-9 ISSN:0027-8874.There is no expanded citation for this reference.229Challapalli, A.; Carroll, L.; Aboagye, E. O. Molecular Mechanisms of Hypoxia in Cancer. Clin. Transl. Imaging 2017, 5, 225– 253, DOI: 10.1007/s40336-017-0231-1[Crossref], [PubMed], [CAS], Google Scholar229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cnmsFGmsA%253D%253D&md5=13a5a815280895929fcb5900c7389309Molecular mechanisms of hypoxia in cancerChallapalli Amarnath; Carroll Laurence; Aboagye Eric OClinical and translational imaging (2017), 5 (3), 225-253 ISSN:2281-5872.PURPOSE: Hypoxia is a condition of insufficient oxygen to support metabolism which occurs when the vascular supply is interrupted, or when a tumour outgrows its vascular supply. It is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. This review provides an overview of hypoxia imaging with Positron emission tomography (PET), with an emphasis on the biological relevance, mechanism of action, highlighting advantages, and limitations of the currently available hypoxia radiotracers. METHODS: A comprehensive PubMed literature search was performed, identifying articles relating to biological significance and measurement of hypoxia, MRI methods, and PET imaging of hypoxia in preclinical and clinical settings, up to December 2016. RESULTS: A variety of approaches have been explored over the years for detecting and monitoring changes in tumour hypoxia, including regional measurements with oxygen electrodes placed under CT guidance, MRI methods that measure either oxygenation or lactate production consequent to hypoxia, different nuclear medicine approaches that utilise imaging agents the accumulation of which is inversely related to oxygen tension, and optical methods. The advantages and disadvantages of these approaches are reviewed, along with individual strategies for validating different imaging methods. PET is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. CONCLUSION: Even though hypoxia could have significant prognostic and predictive value in the clinic, the best method for hypoxia assessment has in our opinion not been realised.230Dewhirst, M. W.; Cao, Y.; Moeller, B. Cycling Hypoxia and Free Radicals Regulate Angiogenesis and Radiotherapy Response. Nat. Rev. Cancer 2008, 8, 425– 437, DOI: 10.1038/nrc2397[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmt1Oksbo%253D&md5=0274e5238dbedb494167f3c882946215Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy responseDewhirst, Mark W.; Cao, Yiting; Moeller, BenjaminNature Reviews Cancer (2008), 8 (6), 425-437CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. Hypoxia and free radicals, such as reactive oxygen and nitrogen species, alter the activity of the transcription factor HIF1, which can regulate tumor cell survival and angiogenesis. Intratumoral heterogeneity of these factors significantly affects HIF1 and consequently the response to cytotoxic therapy. Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumor development. The hypoxic environment of tumors is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumor cell survival. As discussed here, a const. theme emerges: inhibition of HIF1 activity will have therapeutic benefit.231Kushibiki, T.; Hirasawa, T.; Okawa, S.; Ishihara, M. Responses of Cancer Cells Induced by Photodynamic Therapy. J. Healthc. Eng. 2013, 4, 87– 108, DOI: 10.1260/2040-2295.4.1.87[Crossref], [PubMed], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3svnt1CmsQ%253D%253D&md5=d6724d472afa4095180791924c525840Responses of cancer cells induced by photodynamic therapyKushibiki Toshihiro; Hirasawa Takeshi; Okawa Shinpei; Ishihara MiyaJournal of healthcare engineering (2013), 4 (1), 87-108 ISSN:2040-2295.Photodynamic therapy (PDT) involves the administration of a photosensitizer, followed by local irradiation of tumor tissues using a laser of an appropriate wavelength to activate the photosensitizer. Since multiple cellular signaling cascades are concomitantly activated in cancer cells exposed to the photodynamic effect, understanding the responses of cancer cells to PDT will aid in the development of new interventions. This review describes the possible cell-death signaling pathways initiated by PDT. In addition, we describe our latest findings regarding the induction of expression of miRNAs specific to apoptosis in cancer cells and the induction of antitumor immunity following PDT against cancer cells. A more detailed understanding of the molecular mechanisms related to PDT will potentially improve long-term survival of PDT treated patients.232Li, S.; Meng, W.; Guan, Z.; Guo, Y.; Han, X. The Hypoxia-Related Signaling Pathways of Vasculogenic Mimicry in Tumor Treatment. Biomed. Pharmacother. 2016, 80, 127– 135, DOI: 10.1016/j.biopha.2016.03.010[Crossref], [PubMed], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xks1Cmsbw%253D&md5=ae56cd305bf09ab3a8e53843ad146f5dThe hypoxia-related signaling pathways of vasculogenic mimicry in tumor treatmentLi, Shuixian; Meng, Wen; Guan, Ziwei; Guo, Yuanling; Han, XiuzhenBiomedicine & Pharmacotherapy (2016), 80 (), 127-135CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)Tumors require a blood supply for survival, growth, and metastasis. It is widely accepted that the development of the tumor microcirculation compartment need the prodn. of new blood vessels (angiogenesis). Vasculogenic mimicry (VM) is an alternative type of blood supplement independent of endothelial vessels which refers to the formation of tumor cell-lined vessels and is assocd. with tumor invasion, metastasis and poor cancer patient prognosis. Although a variety of proteins and microenvironmental factors are known to contribute to VM, the mechanisms underlying its formation remain unclear. The induction of VM seems to be related to hypoxia, which may promote the plastic, transendothelial phenotype of tumor cells capable of VM. Here, with regard to the above aspects, we review the advanced research on VM including mol. mechanisms and its clin. significance; and explore the development of VM-related strategies which are being utilized for anticancer treatment.233Yao, J.; Feng, J.; Gao, X.; Wei, D.; Kang, T.; Zhu, Q.; Jiang, T.; Wei, X.; Chen, J. Neovasculature and Circulating Tumor Cells Dual-Targeting Nanoparticles for the Treatment of the Highly-Invasive Breast Cancer. Biomaterials 2017, 113, 1– 17, DOI: 10.1016/j.biomaterials.2016.10.033[Crossref], [PubMed], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslCrt7jN&md5=398d22543ae117f01e4fac99a8182684Neovasculature and circulating tumor cells dual-targeting nanoparticles for the treatment of the highly-invasive breast cancerYao, Jianhui; Feng, Jingxian; Gao, Xiaoling; Wei, Dan; Kang, Ting; Zhu, Qianqian; Jiang, Tianze; Wei, Xunbin; Chen, JunBiomaterials (2017), 113 (), 1-17CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Antiangiogenesis therapy has been served as a potent cancer treatment strategy for decades, yet disrupting neovasculature would provoke tumor cells into invasive growth and result in distal metastasis. The basic cause of cancer metastasis can be traced down to the presence of circulating tumor cells (CTCs) which detach from primary tumor site and act as 'seeds'. Epithelial cell adhesion mol. (EpCAM) is a potential biomarker for selective capture of epithelium-derived CTCs. Here, we integrated tumor neovessles-targetable ligands K237 peptide with Ep23 aptamer against EpCAM into a single drug-loaded nanoplatform using paclitaxel (PTX) as the model drug, aiming at damaging the primary tumor and neutralizing CTCs simultaneously to achieve a synergistic anti-tumor therapeutic effect. Enhanced cellular uptake, cell apoptosis-induction and cell-viability inhibition efficiency of the peptide and aptamer dual-functionalized nanoparticles (dTNP) were obsd. in both human umbilical vein endothelial cells (HUVEC) and 4T1 cells in vitro. Using cone-and-plate viscometer to create venous flow velocity, dTNP was also found to be able to capture CTCs under shear stress. The CTC-targeting and neutralization effect of dTNP in bloodstream and 4T1-GFP cell-derived lung metastasis mice model was confirmed via in vivo flow cytometry (IVFC), intravital imaging and confocal microscopy anal. As a result, the orthotropic breast tumor-bearing mice administrated with PTX-loaded dTNP exhibited the optimal therapeutic effect. Taken together, the findings here provided direct evidence that the tumor neovasculature and CTCs dual-targeting drug delivery system could provide a novel modality for the treatment of highly-invasive breast cancer.234Gray, L. H.; Conger, A. D.; Ebert, M.; Hornsey, S.; Scott, O. C. The Concentration of Oxygen Dissolved in Tissues at the Time of Irradiation as a Factor in Radiotherapy. Br. J. Radiol. 1953, 26, 638– 648, DOI: 10.1259/0007-1285-26-312-638[Crossref], [PubMed], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG2cXhvVGjsA%253D%253D&md5=499ec5b0ac6a031247047c40c040f21dThe concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapyGray, L. H.; Conger, A. D.; Ebert, M.; Hornsey, S.; Scott, O. C. A.British Journal of Radiology (1953), 26 (), 638-48CODEN: BJRAAP; ISSN:0007-1285.The sensitivity of tumor cells to x-rays is about 3 times as great when irradiated in a well-oxygenated medium as under anoxic conditions. The manner in which sensitivity depends on O2 tension closely resembles that found by other workers for plant and insect tissues. The sensitivity of the tumor cells to fast neutron radiation is only slightly affected by O2 tension. In certain circumstances the effectiveness of x-ray treatment might be increased if the patient were breathing O2 at the time of irradiation.235Mottram, J. C. A. Factor of Importance in the Radio Sensitivity of Tumours. Br. J. Radiol. 1936, 9, 606– 614, DOI: 10.1259/0007-1285-9-105-606236Arbeit, J. M.; Brown, J. M.; Chao, K. S. C.; Chapman, J. D.; Eckelman, W. C.; Fyles, A. W.; Giaccia, A. J.; Hill, R. P.; Koch, C. J.; Krishna, M. C.; Krohn, K. A.; Lewis, J. S.; Mason, R. P.; Melillo, G.; Padhani, A. R.; Powis, G.; Rajendran, J. G.; Reba, R.; Robinson, S. P.; Semenza, G. L.; Swartz, H. M.; Vaupel, P.; Yang, D.; Tatum, J. L. Hypoxia: Importance in Tumor Biology, Noninvasive Measurement by Imaging, and Value of Its Measurement in the Management of Cancer Therapy. Int. J. Radiat. Biol. 2006, 82, 699– 757, DOI: 10.1080/09553000601002324[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtlejsbnM&md5=8d1221e95c8063c845521b3652782725Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapyTatum, James L.; Kelloff, Gary J.; Gillies, Robert J.; Arbeit, Jeffrey M.; Brown, J. Martin; Chao, K. S. Clifford; Chapman, J. Donald; Eckelman, William C.; Fyles, Anthony W.; Giaccia, Amato J.; Hill, Richard P.; Koch, Cameron J.; Krishna, Murali Cherukuri; Krohn, Kenneth A.; Lewis, Jason S.; Mason, Ralph P.; Melillo, Giovanni; Padhani, Anwar R.; Powis, Garth; Rajendran, Joseph G.; Reba, Richard; Robinson, Simon P.; Semenza, Gregg L.; Swartz, Harold M.; Vaupel, Peter; Yang, David; Croft, Barbara; Hoffman, John; Liu, Guoying; Stone, Helen; Sullivan, DanielInternational Journal of Radiation Biology (2006), 82 (10), 699-757CODEN: IJRBE7; ISSN:0955-3002. (Informa Healthcare)A review. Purpose: The Cancer Imaging Program of the National Cancer Institute convened a workshop to assess the current status of hypoxia imaging, to assess what is known about the biol. of hypoxia as it relates to cancer and cancer therapy, and to define clin. scenarios in which in vivo hypoxia imaging could prove valuable. Results: Hypoxia, or low oxygenation, has emerged as an important factor in tumor biol. and response to cancer treatment. It has been correlated with angiogenesis, tumor aggressiveness, local recurrence, and metastasis, and it appears to be a prognostic factor for several cancers, including those of the cervix, head and neck, prostate, pancreas, and brain. The relationship between tumor oxygenation and response to radiation therapy has been well established, but hypoxia also affects and is affected by some chemotherapeutic agents. Although hypoxia is an important aspect of tumor physiol. and response to treatment, the lack of simple and efficient methods to measure and image oxygenation hampers further understanding and limits their prognostic usefulness. There is no gold std. for measuring hypoxia; Eppendorf measurement of pO2 has been used, but this method is invasive. Recent studies have focused on mol. markers of hypoxia, such as hypoxia inducible factor 1 (HIF-1) and carbonic anhydrase isoenzyme IX (CA-IX), and on developing noninvasive imaging techniques. Conclusions: This workshop yielded recommendations on using hypoxia measurement to identify patients who would respond best to radiation therapy, which would improve treatment planning. This represents a narrow focus, as hypoxia measurement might also prove useful in drug development and in increasing our understanding of tumor biol.237Chapman, J. D.; Franko, A. J.; Sharplin, J. A Marker for Hypoxic Cells in Tumours with Potential Clinical Applicability. Br. J. Cancer 1981, 43, 546– 550, DOI: 10.1038/bjc.1981.79[Crossref], [PubMed], [CAS], Google Scholar237https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXkslKgtLs%253D&md5=f95456131173e62668ec8a3003e634bcA marker for hypoxic cells in tumors with potential clinical applicabilityChapman, J. D.; Franko, A. J.; Sharplin, J.British Journal of Cancer (1981), 43 (4), 546-50CODEN: BJCAAI; ISSN:0007-0920.Autoradiog. studies in multicellular spheroids of Chinese hamster V79 cells and EMT-6 fibrosarcomas following incubation with 50 μM misonidazole-14C (I) for 3 h at 37° indicated that I may be a marker for viable hypoxic cells at concns. not expected to produce radiosensitization or cytotoxicity.238Gallez, B.; Baudelet, C.; Jordan, B. F. Assessment of Tumor Oxygenation by Electron Paramagnetic Resonance: Principles and Applications. NMR Biomed. 2004, 17, 240– 262, DOI: 10.1002/nbm.900[Crossref], [PubMed], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXptFSmsL0%253D&md5=08f48eebabc97de39398ac458dc0fdf1Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applicationsGallez, Bernard; Baudelet, Christine; Jordan, Benedicte F.NMR in Biomedicine (2004), 17 (5), 240-262CODEN: NMRBEF; ISSN:0952-3480. (John Wiley & Sons Ltd.)This review paper attempts to provide an overview of the principles and techniques that are often termed ESR (EPR) oximetry. The paper discusses the potential of such methods and illustrates they have been successfully applied to measure oxygen tension, an essential parameter of the tumor microenvironment. To help the reader understand the motivation for carrying out these measurements, the importance of tumor hypoxia is first discussed: the basic issues of why a tumor is hypoxic, why these hypoxic microenvironments promote processes driving malignant progression and why hypoxia dramatically influences the response of tumors to cytotoxic treatments will be explained. The different methods that have been used to est. the oxygenation in tumors will be reviewed. To introduce the basics of EPR oximetry, the specificity of in vivo EPR will be discussed by comparing this technique with NMR and MRI. The different types of paramagnetic oxygen sensors will be presented, as well as the methods for recording the information (EPR spectroscopy, EPR imaging, dynamic nuclear polarization). Several applications of EPR for characterizing tumor oxygenation will be illustrated, with a special emphasis on pharmacol. interventions that modulate the tumor microenvironment. Finally, the challenges for transposing the method into the clinic will also be discussed.239Kwock, L.; Gill, M.; McMurry, H. L.; Beckman, W.; Raleigh, J. A.; Joseph, A. P. Evaluation of a Fluorinated 2-Nitroimidazole Binding to Hypoxic Cells in Tumor-Bearing Rats by 19F Magnetic Resonance Spectroscopy and Immunohistochemistry. Radiat. Res. 1992, 129, 71, DOI: 10.2307/3577905[Crossref], [PubMed], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XhtVWqsr0%253D&md5=c72a8775ca54ab264e75e1660e1d8d2eEvaluation of a fluorinated 2-nitroimidazole binding to hypoxic cells in tumor-bearing rats by fluorine-19 magnetic resonance spectroscopy and immunohistochemistryKwock, Lester; Gill, Michael; McMurray, Harris L.; Beckman, William; Raleigh, James A.; Joseph, Andrew P.Radiation Research (1992), 129 (1), 71-8CODEN: RAREAE; ISSN:0033-7587.A hexafluorinated 2-nitroimidazole, CCI-103F, was evaluated as a probe for hypoxic tumor cells by in vivo 19F magnetic resonance spectroscopy (MRS). Following initial i.p. injections of the drug in tumor-bearing (Dunning R3327-AT1-Matlylu) rats, 19F spectra were obtained on an Otsuka 2.0T Vivospec spectrometer using a 1.5-cm surface coil. The signal at 1- and 2-h time points indicated initial biodistribution of drug in the tumor. At 4 and 8 h, a progressive increase in signal intensity was obsd., indicating retention of drug within the tumor. Tumor signal remained detectable in 4 of 10 rats at 24 h, indicating possible nitroreductive bioactivation by hypoxic cells. Immunohistochem. of these tumors revealed a staining pattern consistent with labeling of hypoxic cells. No detectable 19F signal was found at 24 h for the other rats, indicating complete washout of unbound drug. Immunohistochem. assessment of these tumors revealed some staining for bound drug at the periphery of necrotic zones. 31P-MRS of the tumors showed good correlation with the presence or absence of hypoxia as evaluated by 19F-MRS, T1- and T2-weighted images, and immunohistochem. These results provide the groundwork for further studies using this misonidazole analog for noninvasive identification of hypoxic tumor cells in vivo by MRS.240Dunn, J. F.; O’Hara, J. A.; Zaim-Wadghiri, Y.; Lei, H.; Meyerand, M. E.; Grinberg, O. Y.; Hou, H.; Hoopes, P. J.; Demidenko, E.; Swartz, H. M. Changes in Oxygenation of Intracranial Tumors With Carbogen: A BOLD MRI and EPR Oximetry Study. J. Magn. Reson. Imaging 2002, 16, 511– 521, DOI: 10.1002/jmri.10192[Crossref], [PubMed], [CAS], Google Scholar240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD38nltlSjuw%253D%253D&md5=cff9bd37a779703af0c998c01c344a89Changes in oxygenation of intracranial tumors with carbogen: a BOLD MRI and EPR oximetry studyDunn Jeff F; O'Hara Julia A; Zaim-Wadghiri Youssef; Lei Hao; Meyerand M Elizabeth; Grinberg Oleg Y; Hou Huagang; Hoopes P Jack; Demidenko Eugene; Swartz Harold MJournal of magnetic resonance imaging : JMRI (2002), 16 (5), 511-21 ISSN:1053-1807.PURPOSE: To examine, using blood oxygen level dependent (BOLD) MRI and EPR oximetry, the changes in oxygenation of intracranial tumors induced by carbogen breathing. MATERIALS AND METHODS: The 9L and CNS-1 intracranial rat tumor models were imaged at 7T, before and during carbogen breathing, using a multi-echo gradient-echo (GE) sequence to map R(2)*. On a different group of 9L tumors, tissue pO(2) was measured using EPR oximetry with lithium phthalocyanine as the oxygen-sensitive material. RESULTS: The average decline in R(2)* with carbogen breathing was 13 +/- 1 s(-1) in the CNS-1 tumors and 29 +/- 4 s(-1) in the 9L tumor. The SI vs. TE decay curves indicate the presence of multiple components in the tumor. Tissue pO(2) in the two 9L tumors measured was 8.6 +/- 0.5 and 3.6 +/- 0.6 mmHg during air breathing, and rose to 20 +/- 7 and 16 +/- 4 mmHg (mean +/- SE) with carbogen breathing. Significant changes were observed by 10 minutes, but changes in pO(2) and R(2)* continued in some subjects over the entire 40 minutes. CONCLUSION: EPR results indicate that glial sarcomas may be radiobiologically hypoxic. Both EPR and BOLD data indicate that carbogen breathing increases brain tumor oxygenation. These data support the use of BOLD imaging to monitor changes in oxygenation in brain tumors.241Landuyt, W.; Hermans, R.; Bosmans, H.; Sunaert, S.; Beatse, E.; Farina, D.; Meijerink, M.; Zhang, H.; Bogaert, W.; Lambin, P.; Marchal, G. BOLD Contrast FMRI of Whole Rodent Tumour During Air or Carbogen Breathing Using Echo-Planar Imaging at 1.5 T. Eur. Radiol. 2001, 11, 2332– 2340, DOI: 10.1007/s003300100996[Crossref], [PubMed], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3MnkvVygsQ%253D%253D&md5=89037d859c0b16c02e7a3f3eb1ae396fBOLD contrast fMRI of whole rodent tumour during air or carbogen breathing using echo-planar imaging at 1.5 TLanduyt W; Hermans R; Bosmans H; Sunaert S; Beatse E; Farina D; Meijerink M; Zhang H; Van Den Bogaert W; Lambin P; Marchal GEuropean radiology (2001), 11 (11), 2332-40 ISSN:0938-7994.The aim of this study was to evaluate the feasibility of functional MR imaging (fMRI) at 1.5 T, exploiting blood oxygenation level-dependent (BOLD) contrast, for detecting changes in whole-tumour oxygenation induced by carbogen (5% CO2+95% O2) inhalation of the host. Adult WAG/Rij rats with rhabdomyosarcomas growing subcutaneously in the lower flank were imaged when tumours reached sizes between 1 and 11 cm3 (n=12). Air and carbogen were alternatively supplied at 2 l/min using a snout mask. Imaging was done on a 1.5-T MR scanner using a T2*-weighted gradient-echo, echo-planar imaging (GE-EPI) sequence. Analysis of the whole-tumour EPI images was based on statistical parametric maps. Voxels with and without signal intensity changes (SIC) were recorded. Significance thresholds were set at p<0.05, corrected for multiple comparisons. In continuous air breathing condition, 3 of 12 tumours showed significant negative SIC and 1 tumour had a clear-cut positive SIC. The remaining tumours showed very little or no change. When switching to carbogen breathing, the SIC were significantly positive in 10 of 12 tumours. Negative SIC were present in 4 tumours, of which three were simultaneously characterised by positive SIC. The overall analysis indicated that 6 of the 12 tumours could be considered as strong positive responders to carbogen. Our research demonstrates the applicability of fMRI GE-EPI at 1.5 T to study whole-tumour oxygenation non-invasively. The observed negative SIC during air condition may reflect the presence of transient hypoxia during these measurements. Selection of tumours on the basis of their individual response to carbogen is possible, indicating a role of such non-invasive measurements for using tailor-made treatments.242Kelada, O. J.; Carlson, D. J. Molecular Imaging of Tumor Hypoxia with Positron Emission Tomography. Radiat. Res. 2014, 181, 335– 349, DOI: 10.1667/RR13590.1[Crossref], [PubMed], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXot12isrw%253D&md5=8b8384fd55777b705a392dcf54ea1533Molecular imaging of tumor hypoxia with positron emission tomographyKelada, Olivia J.; Carlson, David J.Radiation Research (2014), 181 (4), 335-349CODEN: RAREAE; ISSN:0033-7587. (Radiation Research Society)A review. The problem of tumor hypoxia has been recognized and studied by the oncol. community for over 60 years. From radiation and chemotherapy resistance to the increased risk of metastasis, low oxygen concns. in tumors have caused patients with many types of tumors to respond poorly to conventional cancer therapies. It is clear that patients with high levels of tumor hypoxia have a poorer overall treatment response and that the magnitude of hypoxia is an important prognostic factor. As a result, the development of methods to measure tumor hypoxia using invasive and noninvasive techniques has become desirable to the clin. oncol. community. A variety of imaging modalities have been established to visualize hypoxia in vivo. Positron emission tomog. (PET) imaging, in particular, has played a key role for imaging tumor hypoxia because of the development of hypoxia-specific radiolabeled agents. Consequently, this technique is increasingly used in the clinic for a wide variety of cancer types. Following a broad overview of the complexity of tumor hypoxia and measurement techniques to date, this article will focus specifically on the accuracy and reproducibility of PET imaging to quantify tumor hypoxia. Despite numerous advances in the field of PET imaging for hypoxia, we continue to search for the ideal hypoxia tracer to both qual. and quant. define the tumor hypoxic vol. in a clin. setting to optimize treatments and predict response in cancer patients.243Vaupel, P. Tumor Microenvironmental Physiology and Its Implications for Radiation Oncology. Semin. Radiat. Oncol. 2004, 14, 198– 206, DOI: 10.1016/j.semradonc.2004.04.008[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2czltFOrsQ%253D%253D&md5=52dc30f316eac2b99d237f3e2ddbe064Tumor microenvironmental physiology and its implications for radiation oncologyVaupel PeterSeminars in radiation oncology (2004), 14 (3), 198-206 ISSN:1053-4296.The microenvironmental physiology of tumors is uniquely different from that of normal tissues. It is characterized, inter alia, by O(2) depletion (hypoxia, anoxia), glucose and energy deprivation, high lactate levels, and extracellular acidosis, parameters that are anisotropically distributed within the tumor mass. This hostile microenvironment is largely dictated by the abnormal tumor vasculature and heterogeneous microcirculation. Hypoxia and other hostile microenvironmental parameters are known to directly or indirectly confer resistance to irradiation leading to treatment failure. Hypoxia directly leads to a reduced "fixation" of radiation-induced DNA damage. Indirect mechanisms include a restrained proliferation, changes in gene expression and alterations of the proteome (eg, elevated activity of DNA-repair enzymes and resistance-related proteins, increased transcription of growth factors), and genomic changes (genomic instability leading to clonal heterogeneity and selection of resistant clonal variants). These changes, caused by the hostile microenvironment, can favor tumor progression and acquired treatment resistance, both resulting in poor clinical outcome and prognosis. Pretreatment assessment of critical microenvironmental parameters is therefore needed to allow the selection of patients who could benefit from special treatment approaches (eg, hypoxia-targeting therapy). Because of a relatively high risk of local relapse or distant metastasis, patients with hypoxic and/or "high-lactate" tumors should undergo close surveillance.244Mees, G.; Dierckx, R.; Vangestel, C.; Van De Wiele, C. Molecular Imaging of Hypoxia with Radiolabelled Agents. Eur. J. Nucl. Med. Mol. Imaging 2009, 36, 1674– 1686, DOI: 10.1007/s00259-009-1195-9[Crossref], [PubMed], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1WhtLrI&md5=7784884b9f04349674a573fd78897e80Molecular imaging of hypoxia with radiolabelled agentsMees, Gilles; Dierckx, Rudi; Vangestel, Christel; Van de Wiele, ChristopheEuropean Journal of Nuclear Medicine and Molecular Imaging (2009), 36 (10), 1674-1686CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. Tissue hypoxia results from an inadequate supply of oxygen (O2) that compromises biol. functions. Structural and functional abnormalities of the tumor vasculature together with altered diffusion conditions inside the tumor seem to be the main causes of tumor hypoxia. Evidence from exptl. and clin. studies points to a role for tumor hypoxia in tumor propagation, resistance to therapy and malignant progression. This has led to the development of assays for the detection of hypoxia in patients in order to predict outcome and identify patients with a worse prognosis and/or patients that would benefit from appropriate treatments. A variety of invasive and non-invasive approaches have been developed to measure tumor oxygenation including oxygen-sensitive electrodes and hypoxia marker techniques using various labels that can be detected by different methods such as positron emission tomog. (PET), single photon emission computed tomog. (SPECT), magnetic resonance imaging (MRI), autoradiog. and immunohistochem. This review aims to give a detailed overview of non-invasive mol. imaging modalities with radiolabeled PET and SPECT tracers that are available to measure tumor hypoxia.245Lee, S. T.; Scott, A. M. Hypoxia Positron Emission Tomography Imaging With 18F-Fluoromisonidazole. Semin. Nucl. Med. 2007, 37, 451– 461, DOI: 10.1053/j.semnuclmed.2007.07.001[Crossref], [PubMed], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2srpvFClsw%253D%253D&md5=24137699a9739ab35d0758bdd2c87676Hypoxia positron emission tomography imaging with 18f-fluoromisonidazoleLee Sze Ting; Scott Andrew MSeminars in nuclear medicine (2007), 37 (6), 451-61 ISSN:0001-2998.The importance of hypoxia in disease pathogenesis and prognosis is gathering increasing clinical significance and having a greater impact on patient management and outcome. Previous efforts to evaluate hypoxia have included the invasive assessment of hypoxia with immunohistologic and histographic oxygen probes. The emergence of new radiotracers has allowed noninvasive assessment of hypoxia, with the most extensively investigated and validated positron emission tomography radiotracer of hypoxia to date being (18)F-fluoromisonodazole ((18)F-FMISO). This review discusses the relevance and biology of hypoxia in cells and organ systems, and reviews the laboratory and clinical applications of (18)F-FMISO in oncology and noncancer disease states.246Koh, W. J.; Griffin, T. W.; Rasfy, J. S.; Laramore, G. E. Positron Emission Tomography: A New Tool for Characterization of Malignant Disease and Selection of Therapy. Acta Oncol. 1994, 33, 323– 327, DOI: 10.3109/02841869409098424[Crossref], [PubMed], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2c3ovFSgug%253D%253D&md5=1ef63a90dc4b9f55056438af27c24224Positron emission tomography. A new tool for characterization of malignant disease and selection of therapyKoh W J; Griffin T W; Rasey J S; Laramore G EActa oncologica (Stockholm, Sweden) (1994), 33 (3), 323-7 ISSN:0284-186X.Present therapy for cancer patients is based primarily on tumor histology and anatomy. Despite treatment advances, clinicians have often been frustrated by their inability to assess tumor biology. Metabolic imaging by positron emission tomography is a promising new technology that has opened up a whole realm of study in oncology. Glucose metabolism, hemodynamics, oxygen utilization, protein synthesis and thymidine incorporation may yield valuable data regarding tumor aggressiveness and stage, and allow assessment of tumor response early during treatment, before morphological changes are detectable. Other metabolic determinations, including tumor hypoxia and estrogen receptor density, may predict tumor response to therapy, and lead to selection of more appropriate treatment regimens, such as with neutrons or hypoxic cell sensitizers for documentably hypoxic tumors. While further clinical validation is required, positron emission tomography promises to provide vital information complementary to present anatomical imaging modalities that will aid oncologists in optimal management of their patients.247Cortezon-Tamarit, F.; Sarpaki, S.; Calatayud, D. G.; Mirabello, V.; Pascu, S. I. Applications of “Hot” and “Cold” Bis(Thiosemicarbazonato) Metal Complexes in Multimodal Imaging. Chem. Rec. 2016, 16, 1380– 1397, DOI: 10.1002/tcr.201500292[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnsVyrsbk%253D&md5=541f7091360f4fc811271b380ed1c2b4Applications of "Hot" and "Cold" Bis(thiosemicarbazonato) Metal Complexes in Multimodal ImagingCortezon-Tamarit, Fernando; Sarpaki, Sophia; Calatayud, David G.; Mirabello, Vincenzo; Pascu, Sofia I.Chemical Record (2016), 16 (3), 1380-1397CODEN: CRHEAK; ISSN:1528-0691. (Wiley-VCH Verlag GmbH & Co. KGaA)The applications of coordination chem. to mol. imaging has become a matter of intense research over the past 10 years. In particular, the applications of bis(thiosemicarbazonato) metal complexes in mol. imaging have mainly been focused on compds. with aliph. backbones due to the in vivo imaging success of hypoxic tumors with PET (positron emission tomog.) using 64CuATSM [copper (diacetyl-bis(N4-methylthiosemicarbazone))]. This compd. entered clin. trials in the US and the UK during the first decade of the 21st century for imaging hypoxia in head and neck tumors. The replacement of the ligand backbone to arom. groups, coupled with the exocyclic N's functionalization during the synthesis of bis(thiosemicarbazones) opens the possibility to use the corresponding metal complexes as multimodal imaging agents of use, both in vitro for optical detection, and in vivo when radiolabeled with several different metallic species. The greater kinetic stability of acenaphthenequinone bis(thiosemicarbazonato) metal complexes, with respect to that of the corresponding aliph. ATSM complexes, allows the stabilization of a no. of imaging probes, with special interest in "cold" and "hot" Cu(II) and Ga(III) derivs. for PET applications and 111In(III) derivs. for SPECT (single-photon emission computed tomog.) applications, while Zn(II) derivs. display optical imaging properties in cells, with enhanced fluorescence emission and lifetime with respect to the free ligands. Preliminary studies have shown that gallium-based acenaphthenequinone bis(thiosemicarbazonato) complexes are also hypoxia selective in vitro, thus increasing the interest in them as new generation imaging agents for in vitro and in vivo applications.248Hueting, R.; Kersemans, V.; Cornelissen, B.; Tredwell, M.; Hussien, K.; Christlieb, M.; Gee, A. D.; Passchier, J.; Smart, S. C.; Dilworth, J. R.; Gouverneur, V.; Muschel, R. J. A Comparison of the Behavior of 64Cu-Acetate and 64Cu-ATSM in Vitro and in Vivo. J. Nucl. Med. 2014, 55, 128– 134, DOI: 10.2967/jnumed.113.119917[Crossref], [PubMed], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtlCkurs%253D&md5=36ec03664adc886abb76d2884ca36b51A comparison of the behavior of 64Cu-acetate and 64Cu-ATSM in vitro and in vivoHueting, Rebekka; Kersemans, Veerle; Cornelissen, Bart; Tredwell, Matthew; Hussein, Kamila; Christlieb, Martin; Gee, Antony D.; Passchier, Jan; Smart, Sean C.; Dilworth, Jonathan R.; Gouverneur, Veronique; Muschel, Ruth J.Journal of Nuclear Medicine (2014), 55 (1), 128-134CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)64Cu-diacetyl-bis(N4-methylthiosemicarbazonate), 64Cu-ATSM, continues to be investigated clin. as a PET agent both for delineation of tumor hypoxia and as an effective indicator of patient prognosis, but there are still aspects of the mechanism of action that are not fully understood. Methods: The retention of radioactivity in tumors after administration of 64Cu-ATSM in vivo is substantially higher for tumors with a significant hypoxic fraction. This hypoxia-dependent retention is believed to involve the redn. of Cu-ATSM, followed by the loss of copper to cellular copper processing. To shed light on a possible role of copper metab. in hypoxia targeting, we have compared 64Cu retention in vitro and in vivo in CaNT and EMT6 cells or cancers after the administration of 64Cu-ATSM or 64Cu-acetate. Results: In vivo in mice bearing CaNT or EMT6 tumors, biodistributions and dynamic PET data are broadly similar for 64Cu-ATSM and 64Cu-acetate. Copper retention in tumors at 15 min is higher after injection of 64Cu-acetate than 64Cu-ATSM, but similar values result at 2 and 16 h for both. Colocalization with hypoxia as measured by EF5 immunohistochem. is evident for both at 16 h after administration but not at 15 min or 2 h. Interestingly, at 2 h tumor retention for 64Cu-acetate and 64Cu-ATSM, although not colocalizing with hypoxia, is reduced by similar amts. by increased tumor oxygenation due to inhalation of increased O2. In vitro, substantially less uptake is obsd. for 64Cu-acetate, although this uptake had some hypoxia selectivity. Although 64Cu-ATSM is stable in mouse serum alone, there is rapid disappearance of intact complex from the blood in vivo and comparable amts. of serum bound activity for both 64Cu-ATSM and 64Cu-acetate. Conclusion: That in vivo, in the EMT6 and CaNT tumors studied, the distribution of radiocopper from 64Cu-ATSM in tumors essentially mirrors that of 64Cu-acetate suggests that copper metab. may also play a role in the mechanism of selectivity of Cu-ATSM.249Holland, J. P.; Aigbirhio, F. I.; Betts, H. M.; Bonnitcha, P. D.; Burke, P.; Christlieb, M.; Churchill, G. C.; Cowley, A. R.; Dilworth, J. R.; Donnelly, P. S.; Green, J. C.; Peach, J. M.; Vasudevan, S. R.; Warren, J. E. Functionalized Bis(Thiosemicarbazonato) Complexes of Zinc and Copper: Synthetic Platforms Toward Site-Specific Radiopharmaceuticals. Inorg. Chem. 2007, 46, 465– 485, DOI: 10.1021/ic0615628[ACS Full Text], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xhtlekt7rP&md5=b01bd55817ee45019eada793fa571dffFunctionalized Bis(thiosemicarbazonato) Complexes of Zinc and Copper: Synthetic Platforms Toward Site-Specific RadiopharmaceuticalsHolland, Jason P.; Aigbirhio, Franklin I.; Betts, Helen M.; Bonnitcha, Paul D.; Burke, Paul; Christlieb, Martin; Churchill, Grant C.; Cowley, Andrew R.; Dilworth, Jonathan R.; Donnelly, Paul S.; Green, Jennifer C.; Peach, Josephine M.; Vasudevan, Sridhar R.; Warren, John E.Inorganic Chemistry (2007), 46 (2), 465-485CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)Two new types of unsym. bis(thiosemicarbazone) pro-ligands H2L (H2L = I; R3 = Me, E t, Ph, allyl; R4 = NH2, Me, Et) and their neutral zinc and copper complexes ML (M = Zn(II), Cu(II)) have been synthesized. These bifunctional ligands both chelate the metal ions and provide pendant amino groups that can be readily functionalized with biol. active mols. Functionalization has been demonstrated by the synthesis of three water-sol. glucose conjugates of the new zinc(II) bis(thiosemicarbazonato) complexes and their copper(II) analogs have been prepd. in aq. soln. via transmetalation. A range of techniques including NMR, ESR, cyclic voltammetry, high-performance liq. chromatog. (HPLC), UV/vis, and fluorescence emission spectroscopy have been used to characterize the complexes. Four compds. including two zinc(II) complexes have been characterized by X-ray crystallog. The connectivity and conformation of the glucose conjugates have been assigned by NMR spectroscopy. Time-dependent d. functional theory calcns. have been used to assign the electronic transitions of the copper(II) bis(thiosemicarbazonato) chromophore. Two copper-64-radiolabeled complexes including one glucose conjugate have been prepd. and characterized using radio-HPLC and transmetalation is shown to be a viable method for radiolabeling compds. with copper radionuclides. Preliminary cell washout studies have been performed under normoxic conditions and the uptake and intracellular distribution have been studied using confocal fluorescence microscopy.250Fujibayashi, Y.; Taniuchi, H.; Yonekura, Y.; Ohtani, H.; Konishi, J.; Yokoyama, A. Copper-62-ATSM: A New Hypoxia Imaging Agent with High Membrane Permeability and Low Redox Potential. J. Nucl. Med. 1997, 38, 1155– 1160[PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXltFChsL8%253D&md5=343ec3b3b0a1a6e886ddb85bac406496Copper-62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox potentialFujibayashi, Yasuhisa; Taniuchi, Hideyuki; Yonekura, Yoshiharu; Ohtani, Hiroshi; Konishi, Junji; Yokoyama, AkiraJournal of Nuclear Medicine (1997), 38 (7), 1155-1160CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)An ideal hypoxia imaging agent should have high membrane permeability for easy access to intracellular mitochondria and low redox potential to confer stability in normal tissue, but it should be able to be reduced by mitochondria with abnormally high electron concns. in hypoxic cells. In this context, nitroimidazole residues are not considered to be essential. In this study, Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM), a 62Cu-bisthiosemicarbazone complex, with high membrane permeability and low redox potential, was evaluated as a possible hypoxia imaging agent, using ESR spectrometry and the Langendorff isolated perfused rat heart model as well as rat heart left anterior descending occlusion model. Nonradioactive Cu-ATSM was incubated with rat mitochondria, after which redn. of Cu(II) to Cu(I) was measured with ESR. As a model of hypoxic mitochondria, rotenone (Complex I inhibitor)-treated mitochondria were used. In this study, Cu-ATSM was reduced by hypoxic but not by normal mitochondria. Thus, retention of 62Cu-ATSM was studied serially in perfused rat hearts under conditions of normoxia (95% O2 + 5% CO2), hypoxia (95% N2 + 5% CO2) and reoxygenation (95% O2 + 5% CO2). In normoxia and reoxygenation, 62Cu-ATSM injected as a single bolus showed low retention (23.77% and 22.80%, resp.) 15 min after injection, but retention was increased markedly under hypoxic conditions (81.10%). Also, in the in vivo left anterior descending occluded rat heart model, 62Cu-ATSM retention was inversely correlated with accumulation of 201Tl, a relative myocardial blood flow marker.251Sarpaki, S.; Cortezon-Tamarit, F.; De Aguiar, S. R. M. M.; Exner, R. M.; Divall, D.; Arrowsmith, R. L.; Ge, H.; Palomares, F. J.; Carroll, L.; Calatayud, D. G.; Paisey, S. J.; Aboagye, E. O.; Pascu, S. I. Radio- and Nano-Chemistry of Aqueous Ga(III) Ions Anchored onto Graphene Oxide-Modified Complexes. Nanoscale 2020, 12, 6603– 6608, DOI: 10.1039/C9NR10145D[Crossref], [PubMed], [CAS], Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXltVSgsrg%253D&md5=7a6e718a978284508be58b44bd4e0425Radio- and nano-chemistry of aqueous Ga(III) ions anchored onto graphene oxide-modified complexesSarpaki, S.; Cortezon-Tamarit, F.; de Aguiar, S. R. M. M.; Exner, R. M.; Divall, D.; Arrowsmith, R. L.; Ge, H.; Palomares, F. J.; Carroll, L.; Calatayud, D. G.; Paisey, S. J.; Aboagye, E. O.; Pascu, S. I.Nanoscale (2020), 12 (12), 6603-6608CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)The gallium-68 radiolabelling of new functional graphene oxide composites is reported herein along with kinetic stability investigations of the radio-nanohybrids under different environments and insights into their surface characteristics by SEM and XPS. The present work highlights the potential of graphene oxides as nanocarriers for small mols. such as bis(thiosemicarbazonato) complexes to act as multifunctional platforms for rapid and effective radioimaging agent incorporation.252Alam, I.; Arrowsmith, R.; Cortezon-Tamarit, F.; Tyman, F.; Kociok-Köhn, G.; Botchway, S.; Dilworth, J.; Carroll, L.; Aboagye, E.; Pascu, S. Microwave Gallium-68 Radiochemistry for Kinetically Stable Bis(Thiosemicarbazone) Complexes: Structural Investigations and Cellular Uptake Under Hypoxia. Dalt. Trans. 2016, 45, 144– 155, DOI: 10.1039/C5DT02537K253Mirabello, V.; Cortezon-Tamarit, F.; Pascu, S. I. Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-Communicable Diseases. Front. Chem. 2018, 6, 27, DOI: 10.3389/fchem.2018.00027[Crossref], [PubMed], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1egsbrP&md5=674669520202c95b0b06b2e5de7c9950Oxygen sensing, hypoxia tracing and in vivo Imaging with functional metalloprobes for the early detection of non-communicable diseasesMirabello, Vincenzo; Cortezon-Tamarit, Fernando; Pascu, Sofia I.Frontiers in Chemistry (Lausanne, Switzerland) (2018), 6 (), 27/1-27/27CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)A review. Hypoxia has been identified as one of the hallmarks of tumor environments and a prognosis factor in many cancers. The development of ideal chem. probes for imaging and sensing of hypoxia remains elusive. Crucial characteristics would include a measurable response to subtle variations of pO2 in living systems and an ability to accumulate only in the areas of interest (e.g., targeting hypoxia tissues) while exhibiting kinetic stabilities in vitro and in vivo. A sensitive probe would comprise platforms for applications in imaging and therapy for non-communicable diseases (NCDs) relying on sensitive detection of pO2. Just a handful of probes for the in vivo imaging of hypoxia [mainly using positron emission tomog. (PET)] have reached the clin. research stage. Many chem. compds., while presenting promising in vitro results as oxygen-sensing probes, are facing considerable disadvantages regarding their general application in vivo. The mechanisms of action of many hypoxia tracers have not been entirely rationalized, esp. in the case of metallo-probes. An insight into the hypoxia selectivity mechanisms can allow an optimization of current imaging probes candidates and this will be explored hereby. The mechanistic understanding of the modes of action of coordination compds. under oxygen concn. gradients in living cells allows an expansion of the scope of compds. toward in vivo applications which, in turn, would help translate these into clin. applications. We summarize hereby some of the recent research efforts made toward the discovery of new oxygen sensing mols. having a metal-ligand core. We discuss their applications in vitro and/or in vivo, with an appreciation of a plethora of mol. imaging techniques (mainly reliant on nuclear medicine techniques) currently applied in the detection and tracing of hypoxia in the preclin. and clin. setups. The design of imaging/sensing probe for early-stage diagnosis would longer term avoid invasive procedures providing platforms for therapy monitoring in a variety of NCDs and, particularly, in cancers.254Schwartz, J.; Grkovski, M.; Rimner, A.; Schöder, H.; Zanzonico, P. B.; Carlin, S. D.; Staton, K. D.; Humm, J. L.; Nehmeh, S. A. Pharmacokinetic Analysis of Dynamic 18F-Fluoromisonidazole Pet Data in Non-Small Cell Lung Cancer. J. Nucl. Med. 2017, 58, 911– 919, DOI: 10.2967/jnumed.116.180422[Crossref], [PubMed], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVagsLnL&md5=e80855f0d9d8ae1dfb2bfb5c36834b9ePharmacokinetic analysis of dynamic 18F-fluoromisonidazole PET data in non-small cell lung cancerSchwartz, Jazmin; Grkovski, Milan; Rimner, Andreas; Schoder, Heiko; Zanzonico, Pat B.; Carlin, Sean D.; Staton, Kevin D.; Humm, John L.; Nehmeh, Sadek A.Journal of Nuclear Medicine (2017), 58 (6), 911-919CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)Hypoxic tumors exhibit increased resistance to radiation, chem., and immune therapies. 18F-fluoromisonidazole (18F-FMISO) PET is a noninvasive, quant. imaging technique used to evaluate the magnitude and spatial distribution of tumor hypoxia. In this study, pharmacokinetic anal. (PKA) of 18F-FMISO dynamic PET extended to 3 h after injection is reported for the first time, to our knowledge, in stage III-IV non-small cell lung cancer (NSCLC) patients. Methods: Sixteen patients diagnosed with NSCLC underwent 2 PET/CT scans (1-3 d apart) before radiation therapy: a 3-min static 18F-FDG and a dynamic 18F-FMISO scan lasting 168 6 15 min. The latter data were acquired in 3 serial PET/CT dynamic imaging sessions, registered with each other and analyzed using pharmacokinetic modeling software. PKA was performed using a 2-tissue, 3-compartment irreversible model, and kinetic parameters were estd. for the vols. of interest detd. using coregistered 18F-FDG images for both the vol. of interest-averaged and the voxelwise time-activity curves for each patient's lesions, normal lung, and muscle. Results: We derived av. values of 18F-FMISO kinetic parameters for NSCLC lesions as well as for normal lung and muscle. We also investigated the correlation between the trapping rate (k3) and delivery rate (K1), influx rate (Ki) consts., and tissue-to-blood activity concn. ratios (TBRs) for all tissues. Lesions had trapping rates 1.6 times larger, on av., than those of normal lung and 4.4 times larger than those in muscle. Addnl., for almost all cases, k3 and Ki had a significant strong correlation for all tissue types. The TBR-k3 correlation was less straightforward, showing a moderate to strong correlation for only 41% of lesions. Finally, K1-k3 voxelwise correlations for tumors were varied, but neg. for 76% of lesions, globally exhibiting a weak inverse relationship (av. R520.23 6 0.39). However, both normal tissue types exhibited significant pos. correlations for more than 60% of patients, with 41% having moderate to strong correlations (R. 0.5). Conclusion: All lesions showed distinct 18F-FMISO uptake. Variable 18F-FMISO delivery was obsd. across lesions, as indicated by the variable values of the kinetic rate const. K1. Except for 3 cases, some degree of hypoxia was apparent in all lesions based on their nonzero k3 values.255Beck, R.; Röper, B.; Carlsen, J. M.; Huisman, M. C.; Lebschi, J. A.; Andratschke, N.; Picchio, M.; Souvatzoglou, M.; Machulla, M. J.; Piert, M. Pretreatment 18F-Faza Pet Predicts Success of Hypoxia-Directed Radiochemotherapy Using Tirapazamine. J. Nucl. Med. 2007, 48, 973– 980, DOI: 10.2967/jnumed.106.038570[Crossref], [PubMed], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVert7fJ&md5=6eb44d8a35836963557ad40768d4f7bfPretreatment 18F-FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamineBeck, Roswitha; Roeper, Barbara; Carlsen, Janette Maria; Huisman, Marc Cornelis; Lebschi, Julia Aloisia; Andratschke, Nicolaus; Picchio, Maria; Souvatzoglou, Michael; Machulla, Hans-Juergen; Piert, MorandJournal of Nuclear Medicine (2007), 48 (6), 973-980CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)We evaluated the predictive value of PET using the hypoxia tracer 18F-fluoroazomycin arabinoside (18F-FAZA) for success of radiotherapy in combination with tirapazamine, a specific cytotoxin for hypoxic cells. Methods: Imaging was performed on EMT6 tumor-bearing nude mice before allocating mice into 4 groups: radiochemotherapy (RCT: 8 fractions of 4.5 Gy within 4 d combined with tirapazamine, 14 mg/kg), radiotherapy alone (RT), chemotherapy alone (tirapazamine) (CHT), or control. Treatment success was assessed by several tumor growth assays, including tumor growth time from 70 to 500 μL and abs. growth delay (aGD). The median pretreatment 18F-FAZA tumor-to-background ratio served as a discriminator between "hypoxic" and "normoxic" tumors. Results: The mean tumor growth was significantly accelerated in hypoxic control tumors (growth time from 70 to 500 μL, 11.0 d) compared with normoxic control tumors (growth time from 70 to 500 μL, 15.6 d). Whereas RT delayed tumor growth regardless of the level of hypoxia, an additive beneficial therapeutic effect of tirapazamine to RT was obsd. only in hypoxic tumors (aGD, 12.9 d) but not in normoxic tumors (aGD, 6.0 d). Conclusion: This study provides compelling evidence that hypoxia imaging using 18F-FAZA PET is able to predict the success of RCT of tumor-bearing mice using the hypoxia-activated chemotherapeutic agent tirapazamine. Pretreatment 18F-FAZA PET, therefore, offers a way for the individualization of tumor treatment involving radiation. The data suggest that by reserving hypoxia-directed therapy to tumors with high 18F-FAZA uptake, improvement of the therapeutic ratio is possible, as the therapeutic effect of tirapazamine seems to be restricted to hypoxic tumors.256Michalski, M. H.; Chen, X. Molecular Imaging in Cancer Treatment. Eur. J. Nucl. Med. Mol. Imaging 2011, 38, 358– 377, DOI: 10.1007/s00259-010-1569-z[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsFKjsw%253D%253D&md5=a332e28c9ca0610d3c3ea0cb2131ae2bMolecular imaging in cancer treatmentMichalski, Mark H.; Chen, XiaoyuanEuropean Journal of Nuclear Medicine and Molecular Imaging (2011), 38 (2), 358-377CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. The success of cancer therapy can be difficult to predict, as its efficacy is often predicated upon characteristics of the cancer, treatment, and individual that are not fully understood or are difficult to ascertain. Monitoring the response of disease to treatment is therefore essential and has traditionally been characterized by changes in tumor vol. However, in many instances, this singular measure is insufficient for predicting treatment effects on patient survival. Mol. imaging allows repeated in vivo measurement of many crit. mol. features of neoplasm, such as metab., proliferation, angiogenesis, hypoxia, and apoptosis, which can be employed for monitoring therapeutic response. In this review, we examine the current methods for evaluating response to treatment and provide an overview of emerging PET mol. imaging methods that will help guide future cancer therapies.257Bonnitcha, P.; Grieve, S.; Figtree, G. Clinical Imaging of Hypoxia: Current Status and Future Directions. Free Radical Biol. Med. 2018, 126, 296– 312, DOI: 10.1016/j.freeradbiomed.2018.08.019[Crossref], [PubMed], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1Cgs7fM&md5=07c5e00e49b343085f8531ba873f050eClinical imaging of hypoxia: Current status and future directionsBonnitcha, Paul; Grieve, Stuart; Figtree, GemmaFree Radical Biology & Medicine (2018), 126 (), 296-312CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)Tissue hypoxia is a key feature of many important causes of morbidity and mortality. In pathologies such as stroke, peripheral vascular disease and ischemic heart disease, hypoxia is largely a consequence of low blood flow induced ischemia, hence perfusion imaging is often used as a surrogate for hypoxia to guide clin. diagnosis and treatment. Importantly, ischemia and hypoxia are not synonymous conditions as it is not universally true that well perfused tissues are normoxic or that poorly perfused tissues are hypoxic. In pathologies such as cancer, for instance, perfusion imaging and oxygen concn. are less well correlated, and oxygen concn. is independently correlated to radiotherapy response and overall treatment outcomes. In addn., the progression of many diseases is intricately related to maladaptive responses to the hypoxia itself. Thus there is potentially great clin. and scientific utility in direct measurements of tissue oxygenation. Despite this, imaging assessment of hypoxia in patients is rarely performed in clin. settings. This review summarises some of the current methods used to clin. evaluate hypoxia, the barriers to the routine use of these methods and the newer agents and techniques being explored for the assessment of hypoxia in pathol. processes.258Carlin, S.; Zhang, H.; Reese, M.; Ramos, N. N.; Chen, Q.; Ricketts, S. A. A Comparison of the Imaging Characteristics and Microregional Distribution of 4 Hypoxia PET Tracers. J. Nucl. Med. 2014, 55, 515– 521, DOI: 10.2967/jnumed.113.126615[Crossref], [PubMed], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXntleltrc%253D&md5=07f331b8b9fc09f5aaf5cfe3095836c4A comparison of the imaging characteristics and microregional distribution of 4 hypoxia PET tracersCarlin, Sean; Zhang, Hanwen; Reese, Megan; Ramos, Nicholas N.; Chen, Qing; Ricketts, Sally-AnnJournal of Nuclear Medicine (2014), 55 (3), 515-521CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)We compared the imaging characteristics and hypoxia selectivity of 4 hypoxia PET radiotracers (18F-fluoromisonidazole [18F-FMISO], 18F-flortanidazole [18F-HX4], 18F-fluoroazomycin arabinoside [18F-FAZA], and 64Cu-diacetyl-bis(N4-methylsemicarbazone) [64Cu-ATSM]) in a single murine xenograft tumor model condition using small-animal PET imaging and combined ex vivo autoradiog. and fluorescence immunohistochem. Methods: Nude mice bearing SQ20b xenograft tumors were administered 1 of 4 hypoxia PET tracers and images acquired 80-90 min after injection. Frozen sections from excised tumors were then evaluated for tracer distribution using digital autoradiog. and compared with histol. markers of tumor hypoxia (pimonidazole, carbonic anydrase 9 [CA9]) and vascular perfusion (Hoechst 33342). Results: The highest tumor uptake was obsd. with 64Cu-ATSM (max. standardized uptake values [SUVmax], 1.26 ± 0.13) and the lowest with 18F-FAZA (SUVmax, 0.41 ± 0.24). 18F-FMISO and 18F-HX4 had similar intermediate tumor uptake (SUVmax, 0.76 ± 0.38 and 0.65 ± 0.19, resp.). Digital autoradiographs of hypoxia tracer distribution were compared pixel by pixel with images of immunohistochem. strains. The fluorinated nitroimidazoles all showed radiotracer uptake increasing with pimonidazole and CA9 staining. 64Cu-ATSM showed the opposite pattern, with highest radiotracer uptake obsd. in regions with the lowest pimonidazole and CA9 staining. Conclusions: The fluorinated nitroimidazoles showed similar tumor distributions when compared with immunohistochem. markers of hypoxia. Variations in tumor standardized uptake value and normal tissue distribution may det. the most appropriate clin. setting for each tracer. 64Cu-ATSM showed the highest tumor accumulation and little renal clearance. However, the lack of correlation between 64Cu-ATSM distribution and immunohistochem. hypoxia markers casts some doubt on the hypoxia selectivity of 64Cu-ATSM.259Lewis, J.; McCarthy, D.; McCarthy, T.; Fujibayashi, Y.; Welch, M. Evaluation of 64Cu-ATSM In Vitro and In Vivo in a Hypoxic Tumor Model. J. Nucl. Med. 1999, 40, 177– 183[PubMed], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXos1aisA%253D%253D&md5=fa5e3bfe3cc7760173821501ec49e0adEvaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor modelLewis, Jason S.; McCarthy, Deborah W.; McCarthy, Timothy J.; Fujibayashi, Yasuhisa; Welch, Michael J.Journal of Nuclear Medicine (1999), 40 (1), 177-183CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine, Inc.)We have evaluated Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM), an effective marker for the delineation of hypoxic but viable tissue, in vitro in the EMT6 carcinoma cell line under varying degrees of hypoxia and compared it with the flow tracer 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) and the hypoxic tracer 18F-fluoromisonidazole (MISO). We have also compared the uptake of Cu-ATSM and Cu-PTSM in vivo and ex vivo in a murine animal model bearing the EMT6 tumor. Uptake of 64Cu-ATSM, 64Cu-PTSM and 18F-MISO in vitro into EMT6 cells was investigated at the dissolved oxygen concns. of 0, 1 × 103, 5 × 103, 5 × 104 and 2 × 105 ppm. Biodistribution performed at 1, 5, 10, 20 and 40 min compared 64Cu-ATSM with 64Cu-PTSM in BALB/c mice bearing EMT6 tumors. To det. long-term retention of 64Cu-ATSM, biodistribution was also performed at 1, 2 and 4 h. Ex vivo autoradiog. of tumor slices after co-injection of 60Cu-PTSM (60Cu, T1/2 = 23.7 min) and 64Cu-ATSM (64Cu, t1/2 = 12.7 h) into the same animal was performed. After 1 h, 64Cu-ATSM was taken up by EMT6 cells: 90% at 0 ppm, 77% at 1 × 103 ppm, 38% at 5 × 103 ppm, 35% at 5 × 104 ppm and 31% at 2 × 105 ppm. 18F-MISO also showed oxygen concn. dependent uptake, but with lower percentages than 64Cu-ATSM. 64Cu-PTSM showed 83%-85% uptake into the cells after 1 h, independent of oxygen concn. Biodistribution data of 64Cu-ATSM and 64Cu-PTSM showed optimal tumor uptake after 5 and 10 min, resp. (0.76% injected dose (ID)/organ for 64Cu-ATSM and 1.11%ID/organ for 64Cu-PTSM). Ex vivo imaging expts. showed 60Cu-PTSM uniform throughout the EMT6 tumor, but heterogeneous uptake of 64Cu-ATSM, indicative of selective trapping of 64Cu-ATSM into the hypoxic tumor cells. Cu-ATSM exhibits selectivity for hypoxic tumor tissue both in vivo and in vitro and may provide a successful diagnostic modality for the detection of tumor ischemia.260Pérès, E. A.; Toutain, J.; Paty, L. P.; Divoux, D.; Ibazizène, M.; Guillouet, S.; Barré, L.; Vidal, A.; Cherel, M.; Bourgeois, M.; Bernaudin, M.; Valable, S. 64Cu-Atsm/64Cu-Cl2 and Their Relationship to Hypoxia in Glioblastoma: A Preclinical Study. EJNMMI Res. 2019, 9, 114, DOI: 10.1186/s13550-019-0586-6[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisV2ksLbO&md5=cd672e128cf889f2c3a02483df10ddbf64Cu-ATSM/64Cu-Cl2 and their relationship to hypoxia in glioblastoma: a preclinical studyPeres, Elodie A.; Toutain, Jerome; Paty, Louis-Paul; Divoux, Didier; Ibazizene, Meziane; Guillouet, Stephane; Barre, Louisa; Vidal, Aurelien; Cherel, Michel; Bourgeois, Mickael; Bernaudin, Myriam; Valable, SamuelEJNMMI Research (2019), 9 (1), 114CODEN: ERJEAI; ISSN:2191-219X. (Springer GmbH)Here, we first analyzed uptake of Cu-ATSM and its less lipophilic counterpart Cu-Cl2 in the tumor over time in an orthotopic glioblastoma model. An in vitro study was also conducted to investigate the hypoxia-dependent copper uptake in tumor cells. We then further performed a comprehensive ex vivo study to compare 64Cu uptake to hypoxic markers, specific cellular reactions, and also transporter expression. Methods: μPET was performed 14 days (18F-FMISO), 15 days (64Cu-ATSM and 64Cu-Cl2), and 16 days (64Cu-ATSM and 64Cu-Cl2) after C6 cell inoculation. C6 cells were also grown in hypoxic workstation to analyze cellular uptake of Cu complexes in different oxygen levels. Results: In vivo results showed that Cu-ASTM and Cu-Cl2 accumulated in hypoxic areas of the tumors. Cu-ATSM also stained, to a lesser extent, non-hypoxic regions, such as regions of astrogliosis, with high expression of copper transporters and in particular DMT-1 and CTR1, and also characterized by the expression of elevated astrogliosis. Conclusion: In the present study, we show that Cu-complexes undoubtedly accumulate in hypoxic areas of the tumors. This uptake may be the reflection of a direct dependency to a redox metab. and also a reflection of hypoxic-induced overexpression of transporters. We also show that Cu-ATSM also stained non-hypoxic regions such as astrogliosis.261Lewis, J. S.; Sharp, T. L.; Laforest, R.; Fujibayashi, Y.; Welch, M. J. Tumor Uptake of Copper-Diacetyl-Bis(N4-Methylthiosemicarbazone): Effect of Changes in Tissue Oxygenation. J. Nucl. Med. 2001, 42, 655– 661[PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XksFSqt74%253D&md5=621f6dd32bfd748ba86389d0d2ea5535Tumor uptake of copper-diacetyl-bis(n4-methylthiosemicarbazone): Effect of changes in tissue oxygenationLewis, Jason S.; Sharp, Terry L.; Laforest, Richard; Fujibayashi, Yasuhisa; Welch, Michael J.Journal of Nuclear Medicine (2001), 42 (4), 655-661CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)We showed previously that, in vitro, copper-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) uptake is dependent on the oxygen concn. (pO2). We also showed that, in vivo, Cu-ATSM uptake is heterogeneous in animal tumors known to contain hypoxic fractions. This study was undertaken to confirm the pO2 dependence of this selective uptake in vivo by correlating Cu-ATSM uptake with measured tumor pO2. Expts. were performed with the 9L gliosarcoma rat model using a needle oxygen electrode to measure tissue pO2. Using PET and electronic autoradiog., Cu-ATSM uptake was measured in tumor tissue under various pO2 levels. The oxygen concn. within implanted tumors was manipulated by chem. means or by altering the inhaled oxygen content. A good correlation between low pO2 and high Cu-ATSM accumulation was obsd. Hydralazine administration in animals caused a decrease in the av. tumor pO2 from 28.61 ± 8.74 mm Hg to 20.81 ± 7.54 mm Hg in untreated control animals breathing atm. oxygen. It also caused the tumor uptake of Cu-ATSM to increase by 35%. Conversely, in animals breathing 100% oxygen, the av. tumor pO2 increased to 45.88 ± 15.9 mm Hg, and the tumor uptake of Cu-ATSM decreased to 48% of that of the control animals. PET of animals treated in a similar fashion yielded time-activity curves showing significantly higher retention of the tracer in hypoxic tissues than in oxygenated tissues. These data confirm that Cu-ATSM uptake in tissues in vivo is dependent on the tissue pO2, and that significantly greater uptake and retention occur in hypoxic tumor tissue. Therefore, the possible use of Cu-ATSM PET as a prognostic indicator in the management of cancer is further validated.262Colombié, M.; Gouard, S.; Frindel, M.; Vidal, A.; Chérel, M.; Kraeber-Bodéré, F.; Rousseau, C.; Bourgeois, M. Focus on the Controversial Aspects of 64Cu-ATSM in Tumoral Hypoxia Mapping by Pet Imaging. Front. Med. 2015, 2, 58, DOI: 10.3389/fmed.2015.00058[Crossref], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC283js1SntA%253D%253D&md5=5b5c86bc4b45450230b6d3f8df4d3b16Focus on the Controversial Aspects of (64)Cu-ATSM in Tumoral Hypoxia Mapping by PET ImagingColombie Mathilde; Gouard Sebastien; Frindel Mathieu; Vidal Aurelien; Cherel Michel; Rousseau Caroline; Kraeber-Bodere Francoise; Bourgeois MickaelFrontiers in medicine (2015), 2 (), 58 ISSN:2296-858X.Mapping tumor hypoxia is a great challenge in positron emission tomography (PET) imaging as the precise functional information of the biological processes is needed for many effective therapeutic strategies. Tumor hypoxia has been widely reported as a poor prognostic indicator and is often associated with tumor aggressiveness, chemo- and radio-resistance. An accurate diagnosis of hypoxia is a challenge and is crucial for providing accurate treatment for patients' survival benefits. This challenge has led to the emergence of new and novel PET tracers for the functional and metabolic characterization of tumor hypoxia non-invasively. Among these tracers, copper semicarbazone compound [64Cu]-diacetyl-bis(N (4)-methylthiosemicarbazone) (=64Cu-ATSM) has been developed as a tracer for hypoxia imaging. This review focuses on 64Cu-ATSM PET imaging and the concept is presented in two sections. The first section describes its in vitro development and pre-clinical testing and particularly its affinity in different cell lines. The second section describes the controversial reports on its specificity for hypoxia imaging. The review concludes that 64Cu-ATSM - more than a hypoxic tracer, exhibits tracer accumulation in tumor, which is linked to the redox potential and reactive oxygen species. The authors concluded that 64Cu-ATSNM is a marker of over-reduced cell state and thus an indirect marker for hypoxia imaging. The affinity of 64Cu-ATSM for over-reduced cells was observed to be a complex phenomenon. And to provide a definitive and convincing mechanism, more in vivo studies are needed to prove the diagnostic utility of 64Cu-ATSM.263Yuan, H.; Schroeder, T.; Bowsher, J. E.; Hedlund, L. W.; Wong, T.; Dewhirst, M. W. Intertumoral Differences in Hypoxia Selectivity of the PET Imaging Agent 64Cu(II)-Diacetyl-Bis(N4-Methylthiosemicarbazone). J. Nucl. Med. 2006, 47, 989– 998[PubMed], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmtlWmtrg%253D&md5=805152c3ada8861fa94ae0e0a28c16daIntertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-Bis(N4-methylthiosemicarbazone)Yuan, Hong; Schroeder, Thies; Bowsher, James E.; Hedlund, Laurence W.; Wong, Terence; Dewhirst, Mark W.Journal of Nuclear Medicine (2006), 47 (6), 989-998CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Cu-Diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) is a recently developed PET imaging agent for tumor hypoxia. However, its accuracy and reliability for measuring hypoxia have not been fully characterized in vivo. The aim of this study was to evaluate 64Cu-ATSM as a hypoxia PET marker by comparing autoradiog. distributions of 64Cu-ATSM with a well-established hypoxia marker drug, EF5. Methods: R3230 mammary adenocarcinomas (R3230Ac), fibrosarcomas (FSA), and 9L gliomas (9L) were used in the study. EF5 and Hoechst 33342, a vascular perfusion marker, were administered to the animal for immunohistochem. anal. 64Cu-ATSM microPET and autoradiog. were performed on the same animal. The tumor-to-muscle ratio (T/M ratio) and standardized uptake values (SUVs) were characterized for these 3 different types of tumors. Five types of images-microPET, autoradiog., EF5 immunostaining, Hoechst fluorescence vascular imaging, and hematoxylin-andeosin histol.-were superimposed, evaluated, and compared. Results: A significantly higher T/M ratio and SUV were seen for FSA compared with R3230Ac and 9L. Spatial correlation anal. between 64Cu-ATSM autoradiog. and EF5 immunostained images varied between the 3 tumor types. There was close correlation of 64Cu-ATSM uptake and hypoxia in R3230Ac and 9L tumors but not in FSA tumors. Interestingly, elevated 64Cu-ATSM uptake was obsd. in well-perfused areas in FSA, indicating a correlation between 64Cu-ATSM uptake and vascular perfusion as opposed to hypoxia. The same relationship was obsd. with 2 other hypoxia markers, pimonidazole and carbonic anhydrase IX, in FSA tumors. Breathing carbogen gas significantly decreased the hypoxia level measured by EF5 staining in FSA-bearing rats but not the uptake of 64Cu-ATSM. These results indicate that some other 64Cu-ATSM retention mechanisms, as opposed to hypoxia, are involved in this type of tumor. Conclusion: To our knowledge, this study is the first comparison between 64Cu-ATSM uptake and immunohistochem. in these 3 tumors. Although we have shown that 64Cu-ATSM is a valid PET hypoxia marker in some tumor types, but not for all, this tumor type-dependent hypoxia selectivity of 64Cu-ATSM challenges the use of 64Cu-ATSM as a universal PET hypoxia marker. Further studies are needed to define retention mechanisms for this PET marker.264Supuran, C. T. Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors. Metabolites 2017, 7, 48, DOI: 10.3390/metabo7030048[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1Sms70%253D&md5=a5c67e04f04323edb4f0b6701b8f665fCarbonic anhydrase inhibition and the management of hypoxic tumorsSupuran, Claudiu T.Metabolites (2017), 7 (3), 48/1-48/13CODEN: METALU; ISSN:2218-1989. (MDPI AG)Hypoxia and acidosis are salient features of many tumors, leading to a completely different metab. compared to normal cells. Two of the simplest metabolic products, protons and bicarbonate, are generated by the catalytic activity of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), with at least two of its isoforms, CA IX and XII, mainly present in hypoxic tumors. Inhibition of tumor-assocd. CAs leads to an impaired growth of the primary tumors, metastases and reduces the population of cancer stem cells, leading thus to a complex and beneficial anticancer action for this class of enzyme inhibitors. In this review, I will present the state of the art on the development of CA inhibitors (CAIs) targeting the tumor-assocd. CA isoforms, which may have applications for the treatment and imaging of cancers expressing them. Small mol. inhibitors, one of which (SLC-0111) completed Phase I clin. trials, and antibodies (girentuximab, discontinued in Phase III clin. trials) will be discussed, together with the various approaches used to design anticancer agents with a new mechanism of action based on interference with these crucial metabolites, protons and bicarbonate.265Park, W.; Bae, B. Chan; Na, K. A Highly Tumor-Specific Light-Triggerable Drug Carrier Responds to Hypoxic Tumor Conditions for Effective Tumor Treatment. Biomaterials 2016, 77, 227– 234, DOI: 10.1016/j.biomaterials.2015.11.014[Crossref], [PubMed], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVejs77M&md5=25d184cbd0383a45b1483aa4c8af5d0eA highly tumor-specific light-triggerable drug carrier responds to hypoxic tumor conditions for effective tumor treatmentPark, Wooram; Bae, Byoung-chan; Na, KunBiomaterials (2016), 77 (), 227-234CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Light-triggered drug delivery is among the most investigated stimulus-response strategies and has been widely explored in cancer treatment. However, the limited specificity of light-triggered drug delivery reduces the therapeutic efficacy and causes considerable undesirable side effects. In this work, we demonstrate a highly tumor-specific light-triggerable drug carrier (H-LTDC) induced by a combination of internal (i.e., tumor hypoxia) and external stimuli (i.e., light). The doxorubicin (DOX)-loaded H-LTDC was self-assembled from type-1-reactive oxygen species (ROStype1)-mediated degradable chondroitin sulfate (CS) conjugated with a photosensitizer (PS), Pheophorbide-a, which has a spherical shape and a uniform size distribution. Under hypoxic conditions, ROSType1 was mainly generated due to the electron-rich sulfate groups in the polysaccharide backbone. The ROStype1 generated by H-LTDC allowed laser-triggered drug release at low oxygen concns. From the in vitro cytotoxicity tests with colon cancer cells (HCT-116), under laser irradn., DOX-loaded H-LTDCs showed higher toxicity under hypoxic conditions than that under normoxic conditions. In vivo and ex vivo biodistribution studies demonstrated that H-LTDCs selectively accumulated in the tumor tissues. As a result, drug-loaded H-LTDCs exhibited high anti-tumor activity in vivo. Overall, we believe that this approach could represent a promising platform for the treatment of tumor and hypoxia-assocd. diseases without undesirable side effects.266Wilson, W. R.; Hay, M. P. Targeting Hypoxia in Cancer Therapy. Nat. Rev. Cancer 2011, 11, 393– 410, DOI: 10.1038/nrc3064[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmsVGmtbk%253D&md5=60b1b30b6d52120a0a76fba28a8e3429Targeting hypoxia in cancer therapyWilson, William R.; Hay, Michael P.Nature Reviews Cancer (2011), 11 (6), 393-410CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. Hypoxia is a feature of most tumors, albeit with variable incidence and severity within a given patient population. It is a neg. prognostic and predictive factor owing to its multiple contributions to chemoresistance, radioresistance, angiogenesis, vasculogenesis, invasiveness, metastasis, resistance to cell death, altered metab., and genomic instability. Given its central role in tumor progression and resistance to therapy, tumor hypoxia might well be considered the best validated target that has yet to be exploited in oncol. However, despite an explosion of information on hypoxia, there are still major questions to be addressed if the long-standing goal of exploiting tumor hypoxia is to be realized. Here, we review the 2 main approaches, namely bioreductive prodrugs and inhibitors of mol. targets upon which hypoxic cell survival depends. We address the particular challenges and opportunities these overlapping strategies present, and discuss the central importance of emerging diagnostic tools for patient stratification in targeting hypoxia.267Lin, Q.; Bao, C.; Yang, Y.; Liang, Q.; Zhang, D.; Cheng, S.; Zhu, L. Highly Discriminating Photorelease of Anticancer Drugs Based on Hypoxia Activatable Phototrigger Conjugated Chitosan Nanoparticles. Adv. Mater. 2013, 25, 1981– 1986, DOI: 10.1002/adma.201204455[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXit1aht7k%253D&md5=3a5f58376b76109135636d48193e9fcbHighly Discriminating Photorelease of Anticancer Drugs Based on Hypoxia Activatable Phototrigger Conjugated Chitosan NanoparticlesLin, Qiuning; Bao, Chunyan; Yang, Yunlong; Liang, Qiannan; Zhang, Dasheng; Cheng, Shuiyu; Zhu, LinyongAdvanced Materials (Weinheim, Germany) (2013), 25 (14), 1981-1986CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)We have successfully constructed a novel hypoxia-activated one- or two-photon photoresponsive drug-release system based on a nitroimidazole-locked coumarin phototrigger. Compared with common photocontrolled release systems, the TAP (tumor hypoxia-activated phototrigger) exhibits highly discriminating photorelease of anticancer drug to hypoxic tumor cells, but not to aerobic healthy cells. Such a dramatic selectivity for tumor-killing potential is anticipated to achieve unprecedented strides in the development of photocontrolled drug-delivery systems, which will impact future chemotherapy for the treatment of solid tumors in vivo.268Qian, C.; Yu, J.; Chen, Y.; Hu, Q.; Xiao, X.; Sun, W.; Wang, C.; Feng, P.; Shen, Q. D.; Gu, Z. Light-Activated Hypoxia-Responsive Nanocarriers for Enhanced Anticancer Therapy. Adv. Mater. 2016, 28, 3313– 3320, DOI: 10.1002/adma.201505869[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjslGhsLk%253D&md5=9f47b4c6770c1cbe2bebccdc6dfe8cb9Light-Activated Hypoxia-Responsive Nanocarriers for Enhanced Anticancer TherapyQian, Chenggen; Yu, Jicheng; Chen, Yulei; Hu, Quanyin; Xiao, Xuanzhong; Sun, Wujin; Wang, Chao; Feng, Peijian; Shen, Qun-Dong; Gu, ZhenAdvanced Materials (Weinheim, Germany) (2016), 28 (17), 3313-3320CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)A light-activated hypoxia-responsive conjugated polymer-based nanocarrier is developed for efficiently producing singlet oxygen (1O2) and inducing hypoxia to promote release of its cargoes in tumor cells, leading to enhanced antitumor efficacy. This dual-responsive nanocarrier provides an innovative design guideline for enhancing traditional photodynamic therapeutic efficacy integrated with a controlled drug-release modality.269Mitton, D.; Ackroyd, R. A Brief Overview of Photodynamic Therapy in Europe. Photodiagn. Photodyn. Ther. 2008, 5, 103– 111, DOI: 10.1016/j.pdpdt.2008.04.004[Crossref], [PubMed], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVCks7%252FO&md5=42a2c32a628a8c3750307b77bac7d4e2A brief overview of photodynamic therapy in EuropeMitton, D.; Ackroyd, R.Photodiagnosis and Photodynamic Therapy (2008), 5 (2), 103-111CODEN: PPTHBF; ISSN:1572-1000. (Elsevier B.V.)A review. Photodynamic effect was a chance discovery early in the 1900s, demonstrating the lethal effects of light activated chems. on living cells. Although the application of the principles of photodynamic effect to patients' treatment and what became photodynamic therapy (PDT) was practiced in 1960s and 1970s, clin. trials were only started in the 1980s, following successful synthesis of clin. usable photosensitizers (drugs) and the manufg. of light sources. We briefly review and highlight some of the landmarks of the development of clin. PDT in Europe.270Floeth, F. W.; Sabel, M.; Ewelt, C.; Stummer, W.; Felsberg, J.; Reifenberger, G.; Steiger, H. J.; Stoffels, G.; Coenen, H. H.; Langen, K. J. Comparison of 18F-FET PET and 5-ALA Fluorescence in Cerebral Gliomas. Eur. J. Nucl. Med. Mol. Imaging 2011, 38, 731– 741, DOI: 10.1007/s00259-010-1690-z[Crossref], [PubMed], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXivFyksL8%253D&md5=231fd8a7e67e4e6cc7292d9360091c15Comparison of 18F-FET PET and 5-ALA fluorescence in cerebral gliomasFloeth, Frank Willi; Sabel, Michael; Ewelt, Christian; Stummer, Walter; Felsberg, Joerg; Reifenberger, Guido; Steiger, Hans Jakob; Stoffels, Gabriele; Coenen, Heinz Hubert; Langen, Karl-JosefEuropean Journal of Nuclear Medicine and Molecular Imaging (2011), 38 (4), 731-741CODEN: EJNMA6; ISSN:1619-7070. (Springer)Purpose: The aim of the study was to compare presurgical 18F-fluoroethyl-L-tyrosine (18F-FET) uptake and Gd-diethylenetriaminepentaacetic acid (DTPA) enhancement on MRI (Gd) with intraoperative 5-aminolevulinic acid (5-ALA) fluorescence in cerebral gliomas. Methods: 18F-FET positron emission tomog. (PET) was performed in 30 patients with brain lesions suggestive of diffuse WHO grade II or III gliomas on MRI. PET and MRI data were coregistered to guide neuronavigated biopsies before resection. After oral application of 5-ALA, 38 neuronavigated biopsies were taken from predefined tumor areas that were pos. or neg. for 18F-FET or Gd and checked for 5-ALA fluorescence. 18F-FET uptake with a mean tumor to brain ratio ≥1.6 was rated as pos. Results: Of 38 biopsies, 21 corresponded to high-grade glioma tissue (HGG) of WHO grade III (n = 19) or IV (n = 2) and 17 biopsies to low-grade glioma tissue (LGG) of WHO grade II. In biopsies corresponding to HGG, 18F-FET PET was pos. in 86% (18/21), but 5-ALA and Gd in only 57% (12/21). A mismatch between Gd and 5-ALA was obsd. in 6 of 21 cases of HGG biopsy samples (3 Gd-pos./5-ALA-neg. and 3 Gd-neg./5-ALA-pos.). In biopsies corresponding to LGG, 18F-FET was pos. in 41% (7/17), while 5-ALA and Gd were neg. in all but one instance. All tumor areas with 5-ALA fluorescence were pos. on 18F-FET PET. Conclusion: There are differences between 18F-FET and 5-ALA uptake in cerebral gliomas owing to a limited sensitivity of 5-ALA to detect tumor tissue esp. in LGG. 18F-FET PET is more sensitive to detect glioma tissue than 5-ALA fluorescence and should be considered as an addnl. tool in resection planning.271Quirk, B. J.; Brandal, G.; Donlon, S.; Vera, J. C.; Mang, T. S.; Foy, A. B.; Lew, S. M.; Girotti, A. W.; Jogal, S.; LaViolette, P. S.; Connelly, J. M.; Whelan, H. T. Photodynamic Therapy (PDT) for Malignant Brain Tumors - Where Do We Stand?. Photodiagn. Photodyn. Ther. 2015, 12, 530– 544, DOI: 10.1016/j.pdpdt.2015.04.009[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfisV2hug%253D%253D&md5=51773677f7c1fd530c521e62255fa704Photodynamic therapy (PDT) for malignant brain tumors--where do we stand?Quirk Brendan J; Connelly Jennifer M; Brandal Garth; Donlon Steven; Vera Juan Carlos; Mang Thomas S; Foy Andrew B; Lew Sean M; Girotti Albert W; Jogal Sachin; LaViolette Peter S; Whelan Harry TPhotodiagnosis and photodynamic therapy (2015), 12 (3), 530-44 ISSN:.INTRODUCTION: What is the current status of photodynamic therapy (PDT) with regard to treating malignant brain tumors? Despite several decades of effort, PDT has yet to achieve standard of care. PURPOSE: The questions we wish to answer are: where are we clinically with PDT, why is it not standard of care, and what is being done in clinical trials to get us there. METHOD: Rather than a meta-analysis or comprehensive review, our review focuses on who the major research groups are, what their approaches to the problem are, and how their results compare to standard of care. Secondary questions include what the effective depth of light penetration is, and how deep can we expect to kill tumor cells. CURRENT RESULTS: A measurable degree of necrosis is seen to a depth of about 5mm. Cavitary PDT with hematoporphyrin derivative (HpD) results are encouraging, but need an adequate Phase III trial. Talaporfin with cavitary light application appears promising, although only a small case series has been reported. Foscan for fluorescence guided resection (FGR) plus intraoperative cavitary PDT results were improved over controls, but are poor compared to other groups. 5-Aminolevulinic acid-FGR plus postop cavitary HpD PDT show improvement over controls, but the comparison to standard of care is still poor. CONCLUSION: Continued research in PDT will determine whether the advances shown will mitigate morbidity and mortality, but certainly the potential for this modality to revolutionize the treatment of brain tumors remains. The various uses for PDT in clinical practice should be pursued.272Suzuki, H. I.; Katsura, A.; Matsuyama, H.; Miyazono, K. MicroRNA Regulons in Tumor Microenvironment. Oncogene 2015, 34, 3085– 3094, DOI: 10.1038/onc.2014.254[Crossref], [PubMed], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlKrtb7M&md5=2f88e10500d2ea7763a2a4492a82b24dMicroRNA regulons in tumor microenvironmentSuzuki, H. I.; Katsura, A.; Matsuyama, H.; Miyazono, K.Oncogene (2015), 34 (24), 3085-3094CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)A review. Cancer initiation and progression are defined by the behavior of cancer cells per se and the development of tumor tissues, both of which are modulated by crosstalk between cancer cells and the surrounding microenvironment. Advances in cancer research have highlighted the significance of const. evolution of the tumor microenvironment, leading to tumor formation, metastasis and refractoriness to therapy. MicroRNAs (miRNAs) are small non-coding RNAs that function as major players of posttranscriptional gene regulation in diverse biol. processes. They function as both tumor suppressors and promoters in many aspects of the autonomous behavior of cancer cells. Theor., dysfunction in the gene regulatory networks of cancer cells is one of the major driving forces for alterations of ostensibly normal surrounding cells. In this context, the core targets of miRNAs, termed miRNA regulons, are currently being expanded to include various modulators of the tumor microenvironment. Recent advances have highlighted two important roles played by miRNAs in the evolution of tumor microenvironments: miRNAs in tumor cells transform the microenvironment via non-cell-autonomous mechanisms, and miRNAs in neighboring cells stabilize cancer hallmark traits. These observations epitomize the distal and proximal functions of miRNAs in tumor microenvironments, resp. Such regulation by miRNAs affects tumor angiogenesis, immune invasion and tumor-stromal interactions. This review summarizes recent findings on the mechanisms of miRNA-mediated regulation of tumor microenvironments, with a perspective on the design of therapeutic interventions.273Waghorn, P. A.; Jones, M. W.; Theobald, M. B. M.; Arrowsmith, R. L.; Pascu, S. I.; Botchway, S. W.; Faulkner, S.; Dilworth, J. R. Shining Light on the Stability of Metal Thiosemicarbazonate Complexes in Living Cells by FLIM. Chem. Sci. 2013, 4, 1430– 1441, DOI: 10.1039/c2sc21489j[Crossref], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtlymtr4%253D&md5=0ed6032322f73ad8a00cb59979ce8248Shining light on the stability of metal thiosemicarbazonate complexes in living cells by FLIMWaghorn, Philip A.; Jones, Michael W.; Theobald, Mark B. M.; Arrowsmith, Rory L.; Pascu, Sofia I.; Botchway, Stanley W.; Faulkner, Stephen; Dilworth, Jonathan R.Chemical Science (2013), 4 (4), 1430-1441CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Complexes of Cu(II), Ni(II) and Zn(II) have been prepd. with bis(thiosemicarbazonate) ligands bearing a pendant Bodipy fluorophore both with (ATSMBodipy) and without (GTSBodipy) backbone Me groups. Biophys. anal. using steady state confocal laser scanning fluorescence images and excited state fluorescence lifetime imaging microscopy (FLIM) data obtained from live cells under aerobic uptake conditions has uniquely allowed both the spatial distribution and degree of dissocn. of the complexes to be assessed. The CuATSMBodipy complex is virtually intact after 20 min and 1 h whereas the corresponding CuGTSBodipy complex is totally dissocd. The complexes ZnATSMBodipy and NiATSMBodipy show little evidence for dissocn. The relevance of this data to the biomedical applications of bis(thiosemicarbazonate) complexes for imaging applications and implications for the treatment of disease such as Alzheimer's and the PET imaging of hypoxia are discussed.274Nie, S.; Xing, Y.; Kim, G. J.; Simons, J. W. Nanotechnology Applications in Cancer. Annu. Rev. Biomed. Eng. 2007, 9, 257– 288, DOI: 10.1146/annurev.bioeng.9.060906.152025[Crossref], [PubMed], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVehtLbK&md5=c4904039a339482da4a73133587cff24Nanotechnology applications in cancerNie, Shuming; Xing, Yun; Kim, Gloria J.; Simons, Jonathan W.Annual Review of Biomedical Engineering (2007), 9 (), 257-288CODEN: ARBEF7; ISSN:1523-9829. (Annual Reviews Inc.)A review. Cancer nanotechnol. is an interdisciplinary area of research in science, engineering, and medicine with broad applications for mol. imaging, mol. diagnosis, and targeted therapy. The basic rationale is that nanometer-sized particles, such as semiconductor quantum dots and iron oxide nanocrystals, have optical, magnetic, or structural properties that are not available from mols. or bulk solids. When linked with tumor targeting ligands such as monoclonal antibodies, peptides, or small mols., these nanoparticles can be used to target tumor antigens (biomarkers) as well as tumor vasculatures with high affinity and specificity. In the mesoscopic size range of 5-100 nm diam., nanoparticles also have large surface areas and functional groups for conjugating to multiple diagnostic (e.g., optical, radioisotopic, or magnetic) and therapeutic (e.g., anticancer) agents. Recent advances have led to bioaffinity nanoparticle probes for mol. and cellular imaging, targeted nanoparticle drugs for cancer therapy, and integrated nanodevices for early cancer detection and screening. These developments raise exciting opportunities for personalized oncol. in which genetic and protein biomarkers are used to diagnose and treat cancer based on the mol. profiles of individual patients.275McCarthy, J. R. Multifunctional Agents for Concurrent Imaging and Therapy in Cardiovascular Disease. Adv. Drug Delivery Rev. 2010, 62, 1023– 1030, DOI: 10.1016/j.addr.2010.07.004[Crossref], [PubMed], [CAS], Google Scholar275https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVGitb7O&md5=20d0a7885d013bbb4d05b7b29facc768Multifunctional agents for concurrent imaging and therapy in cardiovascular diseaseMcCarthy, Jason R.Advanced Drug Delivery Reviews (2010), 62 (11), 1023-1030CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. The development of agents for the simultaneous detection and treatment of disease has recently gained significant attention. These multifunctional theranostic agents posses a no. of advantages over their monofunctional counterparts, as they potentially allow for the concomitant detn. of agent localization, release, and efficacy. Whereas the development of these agents for use in cancers has received the majority of the attention, their use in cardiovascular disease is steadily increasing. As such, this review summarized some of the most poignant recent advances in the development of theranostic agents for the treatment of this class of diseases.276Warenius, H. M. Technological Challenges of Theranostics in Oncology. Expert Opin. Med. Diagn. 2009, 3, 381– 393, DOI: 10.1517/17530050902893295[Crossref], [PubMed], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXps1Wms7s%253D&md5=2eed0d656c176186154150b461816223Technological challenges of theranostics in oncologyWarenius, Hilmar M.Expert Opinion on Medical Diagnostics (2009), 3 (4), 381-393CODEN: EOMDA9; ISSN:1753-0059. (Informa Healthcare)A review. Background: Although the term theranostics has been coined only fairly recently, attempts to relate the level of biomarkers to therapeutic response in the oncol. clinic go back several decades. After a long period in which a limited no. of individual theranostic mol. biomarkers gained general clin. acceptance, extremely powerful genomic and proteomic technologies have now emerged. Methods: These technologies, reviewed here, promise a potential revolution in our ability to predict therapeutic response in cancer, and by so doing, guide new anticancer drugs more successfully into clin. oncol. practice. A full understanding of the detailed mol. nature of clin. cancer is, however, still evolving. The need for appropriate models of the highly complex disease, against which we are attempting to direct effective therapy more accurately, is also addressed. These should include an understanding of genomic and proteomic heterogeneity, genetic instability and systems biol. models of cancer that take into account recent demonstrations of the vastly increased mutational state of the av. clin. cancer as compared with the normal cell(s) from which it arose. Conclusion: The way forward in theranostics is, arguably, less dependent on further improvements in the already powerful genomic and proteomic technologies themselves than on our improved understanding of how we should apply them to the complex reality of the av. clin. cancer.277Habermeyer, B.; Guilard, R. Some Activities of Porphychem Illustrated by the Applications of Porphyrinoids in PDT, PIT and PDI. Photochem. Photobiol. Sci. 2018, 17, 1675– 1690, DOI: 10.1039/C8PP00222C[Crossref], [PubMed], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFSqurnJ&md5=97483e3612cd1bfb26c77ca5c7443cd1Some activities of PorphyChem illustrated by the applications of porphyrinoids in PDT, PIT and PDIHabermeyer, B.; Guilard, R.Photochemical & Photobiological Sciences (2018), 17 (11), 1675-1690CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)Photodynamic therapy is an innovative approach to treat diverse cancers and diseases that involves the use of photosensitizing agents along with light of an appropriate wavelength to generate cytotoxic reactive oxygen species. Among the collection of potential dye candidates, porphyrinoids (i.e. porphyrins, chlorins, and phthalocyanines) are probably the most promising photosensitizers for PDT applications. This review shows the great potential of these derivs. for their industrial development in the field of health through different applications in photodynamic therapy (PDT), photoimmunotherapy (PIT), ophthalmol., dermatol. and photodynamic inactivation (PDI). The purpose of this survey is also to show the new trends and evolutions in these fields.278Singh, S.; Aggarwal, A.; Bhupathiraju, N. V. S. D. K.; Arianna, G.; Tiwari, K.; Drain, C. M. Glycosylated Porphyrins, Phthalocyanines, and Other Porphyrinoids for Diagnostics and Therapeutics. Chem. Rev. 2015, 115, 10261– 10306, DOI: 10.1021/acs.chemrev.5b00244[ACS Full Text], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVahs7rE&md5=64c404241a7ed4daf5e1c0eb5f4a93adGlycosylated Porphyrins, Phthalocyanines, and Other Porphyrinoids for Diagnostics and TherapeuticsSingh, Sunaina; Aggarwal, Amit; Bhupathiraju, N. V. S. Dinesh K.; Arianna, Gianluca; Tiwari, Kirran; Drain, Charles MichaelChemical Reviews (Washington, DC, United States) (2015), 115 (18), 10261-10306CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Agents involved in photodynamic therapy (PDT) are discussed.279Zhang, Y.; Lovell, J. F. Recent Applications of Phthalocyanines and Naphthalocyanines for Imaging and Therapy. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2017, 9, e1420, DOI: 10.1002/wnan.1420280Shao, S.; Rajendiran, V.; Lovell, J. F. Metalloporphyrin Nanoparticles: Coordinating Diverse Theranostic Functions. Coord. Chem. Rev. 2019, 379, 99– 120, DOI: 10.1016/j.ccr.2017.09.002[Crossref], [PubMed], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFCqs7zK&md5=c273f293d0fbe111c114b514237f966eMetalloporphyrin nanoparticles: Coordinating diverse theranostic functionsShao, Shuai; Rajendiran, Venugopal; Lovell, Jonathan F.Coordination Chemistry Reviews (2019), 379 (), 99-120CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)Metalloporphyrins serve key roles in natural biol. processes and also have demonstrated utility for biomedical applications. They can be encapsulated or grafted in conventional nanoparticles or can self-assemble themselves at the nanoscale. A wide range of metals can be stably chelated either before or after porphyrin nanoparticle formation, without the necessity of any addnl. chelator chem. The addn. of metals can substantially alter a range of behaviors such as modulating phototherapeutic efficacy; conferring responsiveness to biol. stimuli; or providing contrast for magnetic resonance, positron emission or surface enhanced Raman imaging. Chelated metals can also provide a convenient handle for bioconjugation with other mols. via axial coordination. This review provides an overview of some recent biomedical, nanoparticulate approaches involving gain-of-function metalloporphyrins and related mols.281Tsolekile, N.; Nelana, S.; Oluwafemi, O. S. Porphyrin as Diagnostic and Therapeutic Agent. Molecules 2019, 24, 2669, DOI: 10.3390/molecules24142669[Crossref], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVygs7fM&md5=a1705a5ae905ba0031d0f64a10d28b3fPorphyrin as diagnostic and therapeutic agentTsolekile, Ncediwe; Nelana, Simphiwe; Oluwafemi, Oluwatobi SamuelMolecules (2019), 24 (14), 2669CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)The synthesis and application of porphyrins has seen a huge shift towards research in porphyrin bio-mol. based systems in the past decade. The preferential localization of porphyrins in tumors, as well as their ability to generate reactive singlet oxygen and low dark toxicities has resulted in their use in therapeutic applications such as photodynamic therapy. However, their inherent lack of bio-distribution due to water insoly. has shifted research into porphyrin-nanomaterial conjugated systems to address this challenge. This has broadened their bio-applications, viz. bio-sensors, fluorescence tracking, in vivo magnetic resonance imaging (MRI), and positron emission tomog. (PET)/CT imaging to photo-immuno-therapy just to highlight a few. This paper reviews the unique theranostic role of porphyrins in disease diagnosis and therapy. The review highlights porphyrin conjugated systems and their applications. The review ends by bringing current challenges and future perspectives of porphyrin based conjugated systems and their resp. applications into light.282Pucelik, B.; Paczyński, R.; Dubin, G.; Pereira, M. M.; Arnaut, L. G.; Dąbrowski, J. M. Properties of Halogenated and Sulfonated Porphyrins Relevant for the Selection of Photosensitizers in Anticancer and Antimicrobial Therapies. PLoS One 2017, 12, e0185984, DOI: 10.1371/journal.pone.0185984[Crossref], [PubMed], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFegt7nO&md5=2b930b74017f765218702bcdee58bf23Properties of halogenated and sulfonated porphyrins relevant for the selection of photosensitizers in anticancer and antimicrobial therapiesPucelik, Barbara; Paczynski, Robert; Dubin, Grzegorz; Pereira, Mariette M.; Arnaut, Luis G.; Dabrowski, Janusz M.PLoS One (2017), 12 (10), e0185984/1-e0185984/22CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)The impact of substituents on the photochem. and biol. properties of tetraphenylporphyrin-based photosensitizers for photodynamic therapy of cancer (PDT) as well as photodynamic inactivation of microorganisms (PDI) was examd. Spectroscopic and physicochem. properties were related with therapeutic efficacy in PDT of cancer and PDI of microbial cells in vitro. Less polar halogenated, sulfonamide porphyrins were most readily taken up by cells compared to hydrophilic and anionic porphyrins. The uptake and PDT of a hydrophilic porphyrin was significantly enhanced with incorporation in polymeric micelles (Pluronic L121). Photodynamic inactivation studies were performed against Gram-pos. (S. aureus, E. faecalis), Gram-neg. bacteria (E. coli, P. aeruginosa, S. marcescens) and fungal yeast (C. albicans). We obsd. a 6 logs redn. of S. aureus after irradn. (10 J/cm2) in the presence of 20μM of hydrophilic porphyrin, but this was not improved with incorporation in Pluronic L121. A 2-3 logs redn. was obtained for E. coli using similar doses, and a decrease of 3-4 logs was achieved for C. albicans. Rational substitution of tetraphenylporphyrins improves their photodynamic properties and informs on strategies to obtain photosensitizers for efficient PDT and PDI. However, the design of the photosensitizers must be accompanied by the development of tailored drug formulations.283Xie, J.; Lee, S.; Chen, X. Nanoparticle-Based Theranostic Agents. Adv. Drug Delivery Rev. 2010, 62, 1064– 1079, DOI: 10.1016/j.addr.2010.07.009[Crossref], [PubMed], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVGitb7J&md5=87873807b175591d2fa5db581677acb2Nanoparticle-based theranostic agentsXie, Jin; Lee, Seulki; Chen, XiaoyuanAdvanced Drug Delivery Reviews (2010), 62 (11), 1064-1079CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Theranostic nanomedicine is emerging as a promising therapeutic paradigm. It takes advantage of the high capacity of nanoplatforms to ferry cargo and loads onto them both imaging and therapeutic functions. The resulting nanosystems, capable of diagnosis, drug delivery and monitoring of therapeutic response, are expected to play a significant role in the dawning era of personalized medicine, and much research effort was devoted toward that goal. A convenience in constructing such function-integrated agents is that many nanoplatforms are already, themselves, imaging agents. Their well-developed surface chem. makes it easy to load them with pharmaceutics and promote them to be theranostic nanosystems. Iron oxide nanoparticles, quantum dots, carbon nanotubes, gold nanoparticles and silica nanoparticles, were previously well investigated in the imaging setting and are candidate nanoplatforms for building up nanoparticle-based theranostics. In the current article, the authors will outline the progress along this line, organized by the category of the core materials. The authors will focus on construction strategies and will discuss the challenges and opportunities assocd. with this emerging technol.284Lammers, T.; Kiessling, F.; Hennink, W. E.; Storm, G. Nanotheranostics and Image-Guided Drug Delivery: Current Concepts and Future Directions. Mol. Pharmaceutics 2010, 7, 1899– 1912, DOI: 10.1021/mp100228v[ACS Full Text], [CAS], Google Scholar284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1GgurzF&md5=c0f1a26ed421514a5422d162807f38caNanotheranostics and Image-Guided Drug Delivery: Current Concepts and Future DirectionsLammers, Twan; Kiessling, Fabian; Hennink, Wim E.; Storm, GertMolecular Pharmaceutics (2010), 7 (6), 1899-1912CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)A review. Nanomedicine formulations aim to improve the biodistribution and the target site accumulation of systemically applied (chemo-) therapeutics. Various different passively and actively targeted nanomedicines have been evaluated over the years, based e.g. on liposomes, polymers, micelles and antibodies, and a significant amt. of (pre-) clin. evidence has been obtained showing that these 5-200 nm sized carrier materials are able to improve the therapeutic index of low-mol.-wt. drugs. Besides for therapeutic purposes, however, nanomedicine formulations have also been more and more used for imaging applications, as well as, in recent years, for theranostic approaches, i.e. for systems and strategies in which disease diagnosis and therapy are combined. Potential applications of theranostic nanomedicine formulations range from the noninvasive assessment of the biodistribution and the target site accumulation of low-mol.-wt. drugs, and the visualization of drug distribution and drug release at the target site, to the optimization of strategies relying on triggered drug release, and the prediction and real-time monitoring of therapeutic responses. Nanotheranostic systems are consequently considered to be highly suitable systems for (pre-) clin. implementation, not only because they might assist in better understanding various important aspects of the drug delivery process, and in developing better drug delivery systems, but also because they might contribute to realizing the potential of "personalized medicine", and to developing more effective and less toxic treatment regimens for individual patients.285Darwent, J. R.; McCubbin, I.; Phillips, D. Excited Singlet and Triplet State Electron-Transfer Reactions of Aluminium(III) Sulphonated Phthalocyanine. J. Chem. Soc., Faraday Trans. 2 1982, 78, 347– 357, DOI: 10.1039/f29827800347[Crossref], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38Xkt1ejsLY%253D&md5=99b051b32a195d942d385811a2f7c89dExcited singlet and triplet state electron-transfer reactions of aluminum(III) sulfonated phthalocyanineDarwent, James R.; McCubbin, Ian; Phillips, D.Journal of the Chemical Society, Faraday Transactions 2: Molecular and Chemical Physics (1982), 78 (2), 347-57CODEN: JCFTBS; ISSN:0300-9238.Conventional and ns flash photolysis were used to study the excited-state reactions of Al(III) sulfonated phthalocyanine (I) with benzohydroquinone (II), methylologen (III), benzylviologen (IV) and di-Na anthraquinone-2,6-disulfonate (V). The fluorescent state of I was quenched by all of these reagents at rates close to the diffusion-controlled limit; however, no sep. electron-transfer products were detected from the reaction with IV, III, or V despite the electrostatic repulsion between the phthalocyanine and semiquinone radical anions. In contrast, quenching by II produced a transient (τ ≃100 ns), which is attributed to a long-lived geminate ion pair, from which sepd. ions escaped. The triplet state of I did not react with V, IV, or III, but was quenched by O2 and II. Sepd. ions were produced 3 times as efficiently from the triplet-state reaction of I with II than from the excited singlet-state reaction.286Couleaud, P.; Morosini, V.; Frochot, C.; Richeter, S.; Raehm, L.; Durand, J. O. Silica-Based Nanoparticles for Photodynamic Therapy Applications. Nanoscale 2010, 2, 1083– 1095, DOI: 10.1039/c0nr00096e[Crossref], [PubMed], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlOntbjO&md5=1c15cd616d19f245724a4f717685fbc4Silica-based nanoparticles for photodynamic therapy applicationsCouleaud, Pierre; Morosini, Vincent; Frochot, Celine; Richeter, Sebastien; Raehm, Laurence; Durand, Jean-OlivierNanoscale (2010), 2 (7), 1083-1095CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)A review. Silica-based nanoparticles for applications in photodynamic therapy (PDT) have emerged as a promising field for the treatment of cancer. In this review, based on the pathway the photosensitizer is entrapped inside the silica matrix, the different methods for the synthesis of silica-based nanoparticles are described from the pioneering works to the latest achievements which concern multifunctional nanoplatforms, up-converting nanoparticles, two-photon PDT, vectorization and in vivo applications.287Oluwole, D. O.; Nyokong, T. Photophysicochemical Behaviour of Metallophthalocyanines When Doped onto Silica Nanoparticles. Dyes Pigm. 2017, 136, 262– 272, DOI: 10.1016/j.dyepig.2016.08.053[Crossref], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVKqsLvE&md5=d2b9ad0f82a554821e032978a985323ePhotophysicochemical behavior of metallophthalocyanines when doped onto silica nanoparticlesOluwole, David O.; Nyokong, TebelloDyes and Pigments (2017), 136 (), 262-272CODEN: DYPIDX; ISSN:0143-7208. (Elsevier Ltd.)Aluminum(III) chloride 2,9(10),16(17),23(24)-tetra-(4-tert-butylphenoxy)phthalocyanine (1), zinc(II) 2,9(10),16(17),23(24)-tetra-(4-tert-butylphenoxy)phthalocyanine (2), zinc(II) 1,8(11),15(18),22(25)-tetra-(4-tert-butylphenoxy) phthalocyanine (3) and zinc(II) 2,9(10),16(17),23(24)-tetra-(4-carboxylphenoxy) phthalocyanine (4) were doped onto silica nanoparticles (SiNPs). There were no significant changes in fluorescence quantum yields and lifetimes of the metallophthalocyanines ( MPcs) when doped onto SiNPs. The triplet quantum yields of the MPcs alone range from 0.22 to 0.85 and in the presence of SiNPs the values range from 0.17 to 0.89. We obsd. a general decrease of triplet quantum yields of phthalocyanines in the conjugates except for 2 where there was an increase. The values were highly affected by aggregation. Complexes 1 and 3 were highly aggregated when doped onto SiNPs, while 2 and 4 did not show much aggregation.288Tang, L.; Cheng, J. Nonporous Silica Nanoparticles for Nanomedicine Application. Nano Today 2013, 8, 290– 312, DOI: 10.1016/j.nantod.2013.04.007[Crossref], [PubMed], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXptVaht70%253D&md5=1527aaf13e5d08d732e7d35d7426d1e5Nonporous silica nanoparticles for nanomedicine applicationTang, Li; Cheng, JianjunNano Today (2013), 8 (3), 290-312CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)A review. Nanomedicine, the use of nanotechnol. for biomedical applications, has potential to change the landscape of the diagnosis and therapy of many diseases. In the past several decades, the advancement in nanotechnol. and material science has resulted in a large no. of org. and inorg. nanomedicine platforms. Silica nanoparticles (NPs), which exhibit many unique properties, offer a promising drug delivery platform to realize the potential of nanomedicine. Mesoporous silica NPs have been extensively reviewed previously. Here we review the current state of the development and application of nonporous silica NPs for drug delivery and mol. imaging.289Huang, D.; Hung, Y.; Ko, B.; Hsu, S.; Chen, W.; Chien, C.; Tsai, C.; Kuo, C.; Kang, J.; Yang, C.; Mou, C.; Chen, Y. Highly Efficient Cellular Labeling of Mesoporous Nanoparticles in Human Mesenchymal Stem Cells: Implication for Stem Cell Tracking. FASEB J. 2005, 19, 2014– 2016, DOI: 10.1096/fj.05-4288fje[Crossref], [PubMed], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtlSmtb7I&md5=9a5f85d551a9fafedf719e3b9bacfd65Highly efficient cellular labeling of mesoporous nanoparticles in human mesenchymal stem cells: implication for stem cell trackingHuang, Dong-Ming; Hung, Yann; Ko, Bor-Sheng; Hsu, Szu-Chun; Chen, Wei-Hsuan; Chien, Chung-Liang; Tsai, Chih-Pin; Kuo, Chieh-Ti; Kang, Ju-Chiun; Yang, Chung-Shi; Mou, Chung-Yuan; Chen, Yao-ChangFASEB Journal (2005), 19 (14), 2014-2016CODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)Tracking the distribution of stem cells is crucial to their therapeutic use. However, the usage of current vectors in cellular labeling is restricted by their low internalizing efficiency. Here, we reported a cellular labeling approach with a novel vector composed of mesoporous silica nanoparticles (MSNs) conjugated with fluorescein isothiocyanate in human bone marrow mesenchymal stem cells and 3T3-L1 cells, and the mechanism about fluorescein isothiocyanate-conjugated MSNs (FITC-MSNs) internalization was studied. FITC-MSNs were efficiently internalized into mesenchymal stem cells and 3T3-L1 cells even in short-term. incubation. The process displayed a time- and concn.-dependent manner and was dependent on clathrin-mediated endocytosis. In addn., clathrin-dependent endocytosis seemed to play a decisive role on more internalization and longer stay of FITC-MSNs in mesenchymal stem cells than in 3T3-L1 cells. The internalization of FITC-MSNs did not affect the cell viability, proliferation, immunophenotype, and differentiation potential of mesenchymal stem cells, and 3T3-L1 cells. Finally, FITC-MSNs could escape from endolysosomal vesicles and were retained the architectonic integrity after internalization. We conclude that the advantages of biocompatibility, durability, and higher efficiency in internalization suit MSNs to be a better vector for stem cell tracking than others currently used.290Lin, Y. S.; Wu, S. H.; Hung, Y.; Chou, Y. H.; Chang, C.; Lin, M. L.; Tsai, C. P.; Mou, C. Y. Multifunctional Composite Nanoparticles: Magnetic, Luminescent, and Mesoporous. Chem. Mater. 2006, 18, 5170– 5172, DOI: 10.1021/cm061976z[ACS Full Text], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVGmsb%252FO&md5=1e2ee625914562002680df1526310833Multifunctional composite nanoparticles: magnetic, luminescent, and mesoporousLin, Yu-Shen; Wu, Si-Han; Hung, Yann; Chou, Yi-Hsin; Chang, Chen; Lin, Meng-Liang; Tsai, Chih-Pin; Mou, Chung-YuanChemistry of Materials (2006), 18 (22), 5170-5172CODEN: CMATEX; ISSN:0897-4756. (American Chemical Society)A new strategy for synthesis of uniform magnetic/luminescent functional mesoporous silica nanoparticles with well-ordered porous structure and good aq. dispersity have been developed. The potential in biol. application have been evaluated. Preliminary results in the cell uptake expts. was shown.291Slowing, I. I.; Vivero-Escoto, J. L.; Wu, C. W.; Lin, V. S. Y. Mesoporous Silica Nanoparticles as Controlled Release Drug Delivery and Gene Transfection Carriers. Adv. Drug Delivery Rev. 2008, 60, 1278– 1288, DOI: 10.1016/j.addr.2008.03.012[Crossref], [PubMed], [CAS], Google Scholar291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosVOnsrg%253D&md5=29e5282dd605da1070e8db179d012fafMesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriersSlowing, Igor I.; Vivero-Escoto, Juan L.; Wu, Chia-Wen; Lin, Victor S.-Y.Advanced Drug Delivery Reviews (2008), 60 (11), 1278-1288CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. In this review, we highlight the recent research developments of a series of surface-functionalized mesoporous silica nanoparticle (MSN) materials as efficient drug delivery carriers. The synthesis of this type of MSN materials is described along with the current methods for controlling the structural properties and chem. functionalization for biotechnol. and biomedical applications. We summarized the advantages of using MSN for several drug delivery applications. The recent investigations of the biocompatibility of MSN in vitro are discussed. We also describe the exciting progress on using MSN to penetrate various cell membranes in animal and plant cells. The novel concept of gatekeeping is introduced and applied to the design of a variety of stimuli-responsive nanodevices. We envision that these MSN-based systems have a great potential for a variety of drug delivery applications, such as the site-specific delivery and intracellular controlled release of drugs, genes, and other therapeutic agents.292Tsai, C. P.; Hung, Y.; Chou, Y. H.; Huang, D. M.; Hsiao, J. K.; Chang, C.; Chen, Y. C.; Mou, C. Y. High-Contrast Paramagnetic Fluorescent Mesoporous Silica Nanorods as a Multifunctional Cell-Imaging Probe. Small 2008, 4, 186– 191, DOI: 10.1002/smll.200700457[Crossref], [PubMed], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXisFSksro%253D&md5=25b254cbf8dd2bca9643eb632e640483High-contrast paramagnetic fluorescent mesoporous silica nanorods as a multifunctional cell-imaging probeTsai, Chih-Pin; Hung, Yann; Chou, Yi-Hsin; Huang, Dong-Ming; Hsiao, Jong-Kai; Chang, Chen; Chen, Yao-Chang; Mou, Chung-YuanSmall (2008), 4 (2), 186-191CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)A real contrast, multifunctional fluorescent and paramagnetic mesoporous silica nanorods can be used to label both phagocytic and nonphagocytotic cells. The cells can be detected simultaneously by a fluorescence technique and the T1- or T2-weighted modes of magnetic resonance imaging (see picture).293Popat, A.; Hartono, S. B.; Stahr, F.; Liu, J.; Qiao, S. Z.; Lu, G. Q. Mesoporous Silica Nanoparticles for Bioadsorption, Enzyme Immobilisation, and Delivery Carriers. Nanoscale 2011, 3, 2801– 2818, DOI: 10.1039/c1nr10224a[Crossref], [PubMed], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptVahsLk%253D&md5=60822a6c7735a23c91e8ffdf72bb1920Mesoporous silica nanoparticles for bioadsorption, enzyme immobilisation, and delivery carriersPopat, Amirali; Hartono, Sandy Budi; Stahr, Frances; Liu, Jian; Qiao, Shi Zhang; Lu, Gao QingNanoscale (2011), 3 (7), 2801-2818CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)A review. Mesoporous silica nanoparticles (MSNs) provide a non-invasive and biocompatible delivery platform for a broad range of applications in therapeutics, pharmaceuticals and diagnosis. The creation of smart, stimuli-responsive systems that respond to subtle changes in the local cellular environment are likely to yield long term solns. to many of the current drug/gene/DNA/RNA delivery problems. In addn., MSNs have proven to be promising supports for enzyme immobilization, enabling the enzymes to retain their activity, affording them greater potential for wide applications in biocatalysis and energy. This review provides a comprehensive summary of the advances made in the last decade and a future outlook on possible applications of MSNs as nanocontainers for storage and delivery of biomols. The authors discuss some of the important factors affecting the adsorption and release of biomols. in MSNs and review of the cytotoxicity aspects of such nanomaterials. The review also highlights some promising work on enzyme immobilization using mesoporous silica nanoparticles.294Chouikrat, R.; Seve, A.; Vanderesse, R.; Benachour, H.; Barberi-Heyob, M.; Richeter, S.; Raehm, L.; Durand, J.-O.; Verelst, M.; Frochot, C. Non Polymeric Nanoparticles for Photodynamic Therapy Applications: Recent Developments. Curr. Med. Chem. 2012, 19, 781– 792, DOI: 10.2174/092986712799034897[Crossref], [PubMed], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xislelu7w%253D&md5=3e8e004cb6673dc2f2c9becbc97db9b2Non polymeric nanoparticles for photodynamic therapy applications: recent developmentsChouikrat, R.; Seve, A.; Vanderesse, R.; Benachour, H.; Barberi-Heyob, M.; Richeter, S.; Raehm, L.; Durand, J.-O.; Verelst, M.; Frochot, C.Current Medicinal Chemistry (2012), 19 (6), 781-792CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. Photodynamic therapy has emerged as an alternative to chemotherapy and radiotherapy for cancer treatment. Nanoparticles have recently been proposed as effective carriers for photosensitizers. Depending on their chem. compn., these can be used for diagnosis and therapy due to the selective accumulation of the photosensitizer in cancer cells in vitro or in tumors in vivo. Multifunctional nanoplatforms combining several applications within the same nano-object emerge as potential important theranostic tools. This review, based on the chem. nature of the nanoparticles will discuss recent advances in the area of non polymeric nanoparticles for photodynamic therapy applications.295Lucky, S. S.; Soo, K. C.; Zhang, Y. Nanoparticles in Photodynamic Therapy. Chem. Rev. 2015, 115, 1990– 2042, DOI: 10.1021/cr5004198[ACS Full Text], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFCms70%253D&md5=7ab133bd9468b25ea92f45e5a55738c1Nanoparticles in Photodynamic TherapyLucky, Sasidharan Swarnalatha; Soo, Khee Chee; Zhang, YongChemical Reviews (Washington, DC, United States) (2015), 115 (4), 1990-2042CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review of use of nanoparticles in photodynamic therapy in treatment of cancer. Topics covered include principles of photodynamic therapy; mechanisms of tumor cell killing by photodynamic therapy; photosensitizers; types of nanoparticles used in photodynamic therapy; nanoparticles as down-converting photosensitizers; and nanoparticles as energy transducers.296Piao, Y.; Burns, A.; Kim, J.; Wiesner, U.; Hyeon, T. Designed Fabrication of Silica-Based Nanostructured Particle Systems for Nanomedicine Applications. Adv. Funct. Mater. 2008, 18, 3745– 3758, DOI: 10.1002/adfm.200800731[Crossref], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXitlGl&md5=7984ae006d53aa0d8902e0fe0d38c8f2Designed fabrication of silica-based nanostructured particle systems for nanomedicine applicationsPiao, Yuanzhe; Burns, Andrew; Kim, Jaeyun; Wiesner, Ulrich; Hyeon, TaeghwanAdvanced Functional Materials (2008), 18 (23), 3745-3758CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Suitably integrating multiple nanomaterials into nanostructured particle systems with specific combinations of properties has recently attracted significant attention in the research community. In particular, numerous particle systems were designed and fabricated by integrating diverse materials with monodispersed silica nanoparticles. One or more distinct nanomaterials can be assembled on, encapsulated within, or integrated both inside and on the surface of silica nanoparticles using different chemistries and techniques to create multifunctional nanosystems. Research on these particle systems for biomedical applications has progressed rapidly during recent years due to the synergistic advantages of these complexes compared to the use of single components. This feature article surveys recent research progress on the fabrication strategies of these nanoparticle systems and their applications to medical diagnostics and therapy, thereby paving the way for the emerging field of nanomedicine.297Ohulchanskyy, T. Y.; Roy, I.; Goswami, L. N.; Chen, Y.; Bergey, E. J.; Pandey, R. K.; Oseroff, A. R.; Prasad, P. N. Organically Modified Silica Nanoparticles With Covalently Incorporated Photosensitizer for Photodynamic Therapy of Cancer. Nano Lett. 2007, 7, 2835– 2842, DOI: 10.1021/nl0714637[ACS Full Text], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsVKntrc%253D&md5=aebde26a31eef628ff9752cb2a0fc1d7Organically Modified Silica Nanoparticles with Covalently Incorporated Photosensitizer for Photodynamic Therapy of CancerOhulchanskyy, Tymish Y.; Roy, Indrajit; Goswami, Lalit N.; Chen, Yihui; Bergey, Earl J.; Pandey, Ravindra K.; Oseroff, Allan R.; Prasad, Paras N.Nano Letters (2007), 7 (9), 2835-2842CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)The authors report a novel nanoformulation of a photosensitizer (PS), for photodynamic therapy (PDT) of cancer, where the PS mols. are covalently incorporated into organically modified silica (ORMOSIL) nanoparticles. The authors found that the covalently incorporated PS mols. retained their spectroscopic and functional properties and could robustly generate cytotoxic singlet oxygen mols. upon photoirradn. The synthesized nanoparticles are of ultralow size (∼20 nm) and are highly monodispersed and stable in aq. suspension. The advantage offered by this covalently linked nanofabrication is that the drug is not released during systemic circulation, which is often a problem with phys. encapsulation. These nanoparticles are also avidly uptaken by tumor cells in vitro and demonstrate phototoxic action, thereby highlighting their potential in diagnosis and PDT of cancer.298Tang, W.; Xu, H.; Kopelman, R.; A. Philbert, M. Photodynamic Characterization and In Vitro Application of Methylene Blue-Containing Nanoparticle Platforms. Photochem. Photobiol. 2005, 81, 242, DOI: 10.1562/2004-05-24-RA-176.1[Crossref], [PubMed], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjslGmsL4%253D&md5=686cf523c6d67f6135397b9298a523fcPhotodynamic characterization and in vitro application of methylene blue-containing nanoparticle platformsTang, Wei; Xu, Hao; Kopelman, Raoul; Philbert, Martin A.Photochemistry and Photobiology (2005), 81 (Mar./Apr.), 242-249CODEN: PHCBAP; ISSN:0031-8655. (American Society for Photobiology)This article presents the development and characterization of nanoparticles loaded with methylene blue (MB), which are designed to be administered to tumor cells externally and deliver singlet oxygen (1O2) for photodynamic therapy (PDT), i.e. cell kill via oxidative stress to the membrane. We demonstrated the encapsulation of MB, a photosensitizer (PS), in three types of sub-200 nm nanoparticles, composed of polyacrylamide, sol-gel silica and organically modified silicate (ORMOSIL), resp. Induced by light irradn., the entrapped MB generated 1O2, and the produced 1O2 was measured quant. with anthracene-9,10-dipropionic acid, disodium salt, to compare the effects of different matrixes on 1O2 delivery. Among these three different kinds of nanoparticles, the polyacrylamide nanoparticles showed the most efficient delivery of 1O2, but its loading of MB was low. In contrast, the sol-gel nanoparticles had the best MB loading but the least efficient 1O2 delivery. In addn. to investigating the matrix effects, a preliminary in vitro PDT study using the MB-loaded polyacrylamide nanoparticles was conducted on rat C6 glioma tumor cells with pos. photodynamic results. The encapsulation of MB in nanoparticles should diminish the interaction of this PS with the biol. milieu, thus facilitating its systemic administration. Furthermore, the concept of the drug-delivering nanoparticles has been extended to a new type of dynamic nanoplatform (DNP) that only delivers 1O2. This DNP could also be used as a targeted multifunctional platform for combined diagnostics and therapy of cancer.299Biju, V. Chemical Modifications and Bioconjugate Reactions of Nanomaterials for Sensing, Imaging, Drug Delivery and Therapy. Chem. Soc. Rev. 2014, 43, 744– 764, DOI: 10.1039/C3CS60273G[Crossref], [PubMed], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlvFCmsA%253D%253D&md5=215ad49a37d22902f02fa80fcea5f349Chemical modifications and bioconjugate reactions of nanomaterials for sensing, imaging, drug delivery and therapyBiju, VasudevanpillaiChemical Society Reviews (2014), 43 (3), 744-764CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. As prepd. nanomaterials of metals, semiconductors, polymers and carbon often need surface modifications such as ligand exchange, and chem. and bioconjugate reactions for various biosensor, bioanal., bioimaging, drug delivery and therapeutic applications. Such surface modifications help us to control the physico-chem., toxicol. and pharmacol. properties of nanomaterials. Furthermore, introduction of various reactive functional groups on the surface of nanomaterials allows us to conjugate a spectrum of contrast agents, antibodies, peptides, ligands, drugs and genes, and construct multifunctional and hybrid nanomaterials for the targeted imaging and treatment of cancers. This tutorial review is intended to provide an introduction to newcomers about how chem. and bioconjugate reactions transform the surface of nanomaterials such as silica nanoparticles, gold nanoparticles, gold quantum clusters, semiconductor quantum dots, carbon nanotubes, fullerene and graphene, and accordingly formulate them for applications such as biosensing, bioimaging, drug and gene delivery, chemotherapy, photodynamic therapy and photothermal therapy. Nonetheless, controversial reports and our growing concerns about toxicity and pharmacokinetics of nanomaterials suggest the need for not only rigorous in vivo expts. in animal models but also novel nanomaterials for practical applications in the clin. settings. Further reading of original and review articles cited herein is necessary to buildup in-depth knowledge about the chem., bioconjugate chem. and biol. applications of individual nanomaterials.300Castilho, M. L.; Vieira, L. S.; Campos, A. P. C.; Achete, C. A.; Cardoso, M. A. G.; Raniero, L. The Efficiency Analysis of Gold Nanoprobes by FT-IR Spectroscopy Applied to the Non-Cross-Linking Colorimetric Detection of Paracoccidioides Brasiliensis. Sens. Actuators, B 2015, 215, 258– 265, DOI: 10.1016/j.snb.2015.03.052[Crossref], [CAS], Google Scholar300https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmt1yqsbc%253D&md5=6b99d039c05505513573b08c3e3733d2The efficiency analysis of gold nanoprobes by FT-IR spectroscopy applied to the non-cross-linking colorimetric detection of Paracoccidioides brasiliensisCastilho, M. L.; Vieira, L. S.; Campos, A. P. C.; Achete, C. A.; Cardoso, M. A. G.; Raniero, L.Sensors and Actuators, B: Chemical (2015), 215 (), 258-265CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)Nanodiagnostics have become an important tool for the development of new methods for clin. and lab. diagnosis. Non-crosslinking colorimetric detection is a promising technique using thiol-modified oligonucleotides (probes) functionalized gold nanoparticles. The nanoprobes allow the detection of a specific sequence of complementary DNA (cDNA) for a well-characterized antigenic protein 27 kDa (p27), which is capable of reacting with the serum of 91% of the patients infected with fungus Paracoccidioides brasiliensis the etiol. agent of Paracoccidioidomycosis. In this work nanoprobe groups were synthesized with final concn. of 33.6 nM, 66.1 nM and 128.1 nM thiolated oligonucleotides. To evaluate the efficiency of the nanoprobes Fourier Transform IR (FT-IR) was used to identify the functional groups of the probe and its bond to the gold nanoparticle. The region between 200 cm-1 and 280 cm-1 corresponds to the Au-S bond, which is a detg. factor for the efficiency of colorimetric detection. The FT-IR results are corroborated with images taken with the Transmission Electron Microscopy (TEM) technique, where the difference between functionalization groups is evident. Considering these aspects, the present work aims to develop a new mol. diagnosis of the fungus Paracoccidioides brasiliensis by non-crosslinking colorimetric detection method using a probe from p27 antigenic cDNA sequence. The non-crosslinking colorimetric diagnostic test possesses 84.4% sensitivity and 81.2% specificity, and may be implemented as clin. diagnosis with simple execution and reasonable cost to effectively detect of Paracoccidioides brasiliensis.301Khaing Oo, M. K.; Yang, Y.; Hu, Y.; Gomez, M.; Du, H.; Wang, H. Gold Nanoparticle-Enhanced and Size-Dependent Generation of Reactive Oxygen Species from Protoporphyrin IX. ACS Nano 2012, 6, 1939– 1947, DOI: 10.1021/nn300327c[ACS Full Text], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjt1Srt7w%253D&md5=c3707a9f91a0fc17975f44278bb13762Gold Nanoparticle-Enhanced and Size-Dependent Generation of Reactive Oxygen Species from Protoporphyrin IXKhaing Oo, Maung Kyaw; Yang, Yamin; Hu, Yue; Gomez, Maria; Du, Henry; Wang, HongjunACS Nano (2012), 6 (3), 1939-1947CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Photosensitizer, protoporphyrin IX (PpIX), was conjugated with Au nanoparticles (Au NPs) of 19, 66, and 106 nm diam. to study the size-dependent enhancement of reactive oxygen species (ROS) formation enabled by Au NPs. The ROS enhancement ratio is detd. to be 1:2.56:4.72 in order of increasing Au NP size, in general agreement with theor. calcd. field enhancement to the fourth power. The convergence of the exptl. and simulated results suggests that Au NP-enhanced and size-dependent ROS formation can be attributed directly to the localized electromagnetic field as a result of surface plasmonic resonance of Au NPs under light irradn. In vitro study on the ROS formation enabled by PpIX-conjugated Au NPs in human breast cancer cells (MDA-MB-231) revealed the similar size-dependent enhancement of intracellular ROS formation, while the enhancement greatly depended on cellular uptake of Au NPs. Cellular photodynamic therapy revealed that cell destruction significantly increased in the presence of Au NPs. Compared to the untreated control (0% destruction), 22.6% cell destruction was seen in the PpIX alone group and more than 50% cell destruction was obtained for all PpIX-conjugated Au NPs. The 66 nm Au NPs yielded the highest cell destruction, consistent with the highest cellular uptake and highest ROS formation. Clearly, the complex cellular environment, size-dependent cellular uptake of Au NPs, and ROS generations are vital contributors to the overall cellular PDT efficacy.302Amini, S. M.; Kharrazi, S.; Hadizadeh, M.; Fateh, M.; Saber, R. Effect of Gold Nanoparticles on Photodynamic Efficiency of 5-Aminolevolenic Acid Photosensitiser in Epidermal Carcinoma Cell Line: An In Vitro Study. IET Nanobiotechnol. 2013, 7, 151– 156, DOI: 10.1049/iet-nbt.2013.0021[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFWks7vK&md5=cbdc93606ef3fe79524a71f7550df11dEffect of gold nanoparticles on photodynamic efficiency of 5-aminolevolenic acid photosensitiser in epidermal carcinoma cell line: an in vitro studyAmini, Seyed Mohammad; Kharrazi, Sharmin; Hadizadeh, Mahnaz; Fateh, Mohsen; Saber, RezaIET Nanobiotechnology (2013), 7 (4), 151-156CODEN: INEACX; ISSN:1751-8741. (Institution of Engineering and Technology)In the recent years, enhanced functionality of treatment systems based on nanostructures has attracted a lot of interest. Photodynamic therapy (PDT) is one such treatment method. Here, the authors report the results of the investigations on synthesis and characterization of gold nanoparticles (GNPs) and their application in PDT along with 5-aminolevolenic acid (5-ALA) (as photosensitizer) with no conjugation. Three sizes of GNPs were synthesized and their cytotoxicity was investigated by using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay on epidermal carcinoma cell line. The results showed that the PDT efficiency of ALA increased in presence of GNPs. This effect was more considerable for 4 nm particles.303Pasparakis, G. Light-Induced Generation of Singlet Oxygen by Naked Gold Nanoparticles and Its Implications to Cancer Cell Phototherapy. Small 2013, 9, 4130– 4134, DOI: 10.1002/smll.201301365[Crossref], [PubMed], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVaktbbF&md5=99a30f76c00b8eb43bc463b156a245cfLight-Induced Generation of Singlet Oxygen by Naked Gold Nanoparticles and its Implications to Cancer Cell PhototherapyPasparakis, GeorgeSmall (2013), 9 (24), 4130-4134CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)Gold nanoparticles were found to generate singlet oxygen after irradn. with pulse laser. Their potential use in cancer phototherapy is discused.304Sherwani, M. A.; Tufail, S.; Khan, A. A.; Owais, M. Gold Nanoparticle-Photosensitizer Conjugate Based Photodynamic Inactivation of Biofilm Producing Cells: Potential for Treatment of C. Albicans Infection in BALB/c Mice. PLoS One 2015, 10, e0131684, DOI: 10.1371/journal.pone.0131684305Penon, O.; Marín, M. J.; Russell, D. A.; Pérez-García, L. Water Soluble, Multifunctional Antibody-Porphyrin Gold Nanoparticles for Targeted Photodynamic Therapy. J. Colloid Interface Sci. 2017, 496, 100– 110, DOI: 10.1016/j.jcis.2017.02.006[Crossref], [PubMed], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXivVKmt7o%253D&md5=ca69d57f51d0720a8318eab71cd099a5Water soluble, multifunctional antibody-porphyrin gold nanoparticles for targeted photodynamic therapyPenon, Oriol; Marin, Maria J.; Russell, David A.; Perez-Garcia, LluisaJournal of Colloid and Interface Science (2017), 496 (), 100-110CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)Photodynamic therapy (PDT) is a treatment of cancer by which tumor cells are destroyed using reactive oxygen species produced by photosensitizers following activation with visible or near IR light. Successful PDT depends on the soly. and the targeting ability of the photosensitizers. In this work, the synthesis of a porphyrin-based water sol. nanoparticle conjugate contg. a targeting agent that recognizes the erbB2 receptor overexpressed on the surface of particular cancer cells is reported. The nanoparticle conjugates were synthesized following two different protocols, viz. a biphasic and a monophasic method, with the aim to det. which method yielded the optimal nanosystem for potential PDT applications. The nanoparticles were characterized using UV-Vis absorption and fluorescence spectroscopies together with transmission electron microscopy and zeta potential measurements; and their ability to produce singlet oxygen following irradn. was investigated following the decay in absorption of a singlet oxygen probe. The nanoparticles synthesized using the monophasic method were shown to produce the highest amt. of singlet oxygen and were further functionalized with anti-erbB2 antibody to target the erbB2 receptors expressed on the surface of SK-BR-3 human breast cancer cells. The water sol., antibody-porphyrin nanoparticle conjugates were shown to elicit targeted PDT of the breast cancer cells.306Basu, S.; Alavi, A. SPECT-CT and PET-CT in Oncology - An Overview. Curr. Med. Imaging Rev. 2011, 7, 202– 209, DOI: 10.2174/157340511796411168307Chopra, A.; Shan, L.; Eckelman, W. C.; Leung, K.; Menkens, A. E. Important Parameters to Consider for the Characterization of PET and SPECT Imaging Probes. Nucl. Med. Biol. 2011, 38, 1079– 1084, DOI: 10.1016/j.nucmedbio.2011.05.011[Crossref], [PubMed], [CAS], Google Scholar307https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFOnsLzN&md5=62d1f0caf22bdde1b1cbd70a701e08a1Important parameters to consider for the characterization of PET and SPECT imaging probesChopra, Arvind; Shan, Liang; Eckelman, William C.; Leung, Kam; Menkens, Anne E.Nuclear Medicine and Biology (2011), 38 (8), 1079-1084CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)There is no expanded citation for this reference.308Frangioni, J. V. In Vivo Near-Infrared Fluorescence Imaging. Curr. Opin. Chem. Biol. 2003, 7, 626– 634, DOI: 10.1016/j.cbpa.2003.08.007[Crossref], [PubMed], [CAS], Google Scholar308https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXot12hsL0%253D&md5=6d10740d915f2372ac60a811c357ddb5In vivo near-infrared fluorescence imagingFrangioni, John V.Current Opinion in Chemical Biology (2003), 7 (5), 626-634CODEN: COCBF4; ISSN:1367-5931. (Elsevier Science Ltd.)A review. Photon penetration into living tissue is highly dependent on the absorption and scattering properties of tissue components. The near-IR region of the spectrum offers certain advantages for photon penetration, and both org. and inorg. fluorescence contrast agents are now available for chem. conjugation to targeting mols. This review focuses on those parameters that affect image signal and background during in vivo imaging with near-IR light and exogenous contrast agents. Recent examples of in vivo near-IR fluorescence imaging of animals and humans are presented, including imaging of normal and diseased vasculature, tissue perfusion, protease activity, hydroxyapatite and cancer.309Ntziachristos, V.; Bremer, C.; Weissleder, R. Fluorescence Imaging With Near-Infrared Light: New Technological Advances That Enable in Vivo Molecular Imaging. Eur. Radiol. 2003, 13, 195– 208, DOI: 10.1007/s00330-002-1524-x[Crossref], [PubMed], [CAS], Google Scholar309https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s%252FjtlKgtg%253D%253D&md5=4a782489ce6a4bf19358d7004cc9c592Fluorescence imaging with near-infrared light: new technological advances that enable in vivo molecular imagingNtziachristos Vasilis; Bremer Christoph; Weissleder RalphEuropean radiology (2003), 13 (1), 195-208 ISSN:0938-7994.A recent development in biomedical imaging is the non-invasive mapping of molecular events in intact tissues using fluorescence. Underpinning to this development is the discovery of bio-compatible, specific fluorescent probes and proteins and the development of highly sensitive imaging technologies for in vivo fluorescent detection. Of particular interest are fluorochromes that emit in the near infrared (NIR), a spectral window, whereas hemoglobin and water absorb minimally so as to allow photons to penetrate for several centimetres in tissue. In this review article we concentrate on optical imaging technologies used for non-invasive imaging of the distribution of such probes. We illuminate the advantages and limitations of simple photographic methods and turn our attention to fluorescence-mediated molecular tomography (FMT), a technique that can three-dimensionally image gene expression by resolving fluorescence activation in deep tissues. We describe theoretical specifics, and we provide insight into its in vivo capacity and the sensitivity achieved. Finally, we discuss its clinical feasibility.310Peng, C.-L.; Shih, Y.-H.; Lee, P.-C.; Hsieh, T. M.-H.; Luo, T.-Y.; Shieh, M.-J. Multimodal Image-Guided Photothermal Therapy Mediated by 188Re-Labeled Micelles Containing a Cyanine-Type Photosensitizer. ACS Nano 2011, 5, 5594– 5607, DOI: 10.1021/nn201100m[ACS Full Text], [CAS], Google Scholar310https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnvVarsr4%253D&md5=bf19fd5e33a7b667f9bfea57fa4aa916Multimodal Image-Guided Photothermal Therapy Mediated by 188Re-Labeled Micelles Containing a Cyanine-Type PhotosensitizerPeng, Cheng-Liang; Shih, Ying-Hsia; Lee, Pei-Chi; Hsieh, Thomas Mon-Hsian; Luo, Tsai-Yueh; Shieh, Ming-JiumACS Nano (2011), 5 (7), 5594-5607CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Multifunctional micelles loaded with the near-IR (NIR) dye and labeled with the radionuclide rhenium-188 (188Re) have been developed to provide multimodalities for NIR fluorescence and nuclear imaging and for photothermal therapy (PTT) of cancer. The NIR dye, IR-780 iodide, allowed the micelles to have dual functions in cancer NIR imaging and PTT. The 188Re-labeled IR-780 micelles enabled imaging by NIR fluorescence and by microSPECT to guide the delivery of drugs and to monitor in real-time the tumor accumulation, intratumoral distribution, and kinetics of drug release, which serve as a basis of specific photothermal injury to the targeted tissue. We also investigated the biodistribution, generation of heat, and photothermal cancer ablation of IR-780 micelles of both in vitro and in vivo xenografts. Histopathol. obsd. irreversible tissue damage, such as necrotic features, decreased cell proliferation, increased apoptosis of cells, and increased expression of heat shock proteins in the PTT-treated tumors. The 188Re-labeled IR-780 micelles offer multifunctional modalities for NIR fluorescence and nuclear imaging and for PTT of cancer.311Shen, X.; Li, L.; Wu, H.; Yao, S. Q.; Xu, Q. H. Photosensitizer-Doped Conjugated Polymer Nanoparticles for Simultaneous Two-Photon Imaging and Two-Photon Photodynamic Therapy in Living Cells. Nanoscale 2011, 3, 5140– 5146, DOI: 10.1039/c1nr11104c[Crossref], [PubMed], [CAS], Google Scholar311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFCmtL7M&md5=83ad09b7622310c1e1476af43392ba97Photosensitizer-doped conjugated polymer nanoparticles for simultaneous two-photon imaging and two-photon photodynamic therapy in living cellsShen, Xiaoqin; Li, Lin; Wu, Hao; Yao, Shao Q.; Xu, Qing-HuaNanoscale (2011), 3 (12), 5140-5146CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)Photosensitizer doped conjugated polymer nanoparticles have been prepd. by incorporating polyoxyethylene nonylphenylether (CO-520) into the nanoparticles using a re-pptn. method. The conjugated polymer, poly[9,9-dibromohexylfluorene-2,7-ylenethylene-alt-1,4-(2,5-dimethoxy)phenylene] (PFEMO), was used as the host matrix to disperse tetraphenylporphyrin (TPP) and an energy donor to enhance the two-photon excitation properties of TPP. These CO-520 incorporated, TPP-doped PFEMO nanoparticles are stable and have low cytotoxicity in the dark. The TPP emission of the nanoparticles was found to be enhanced by about 20 times by PFEMO under two-photon excitation. The nanoparticles showed significantly enhanced two-photon excitation singlet oxygen generation efficiency and two-photon photodynamic therapy activity in cancer cells. These composite nanoparticles display features required for ideal photosensitizers, such as low cytotoxicity in the dark and efficient two-photon photodynamic activity under laser radiation. In addn., these novel nano-photosensitizers allow simultaneous in vivo monitoring by two-photon fluorescence imaging during two-photon photodynamic treatment. These photosensitizer-doped conjugated polymer nanoparticles can act as novel photosensitizing agents for two-photon photodynamic therapy and related applications.312Tian, J.; Ding, L.; Xu, H. J.; Shen, Z.; Ju, H.; Jia, L.; Bao, L.; Yu, J. S. Cell-Specific and PH-Activatable Rubyrin-Loaded Nanoparticles for Highly Selective Near-Infrared Photodynamic Therapy Against Cancer. J. Am. Chem. Soc. 2013, 135, 18850– 18858, DOI: 10.1021/ja408286k[ACS Full Text], [CAS], Google Scholar312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVKjt77M&md5=57b349edb81bf882eb869aac21bf9586Cell-Specific and pH-Activatable Rubyrin-Loaded Nanoparticles for Highly Selective Near-Infrared Photodynamic Therapy against CancerTian, Jiangwei; Ding, Lin; Xu, Hai-Jun; Shen, Zhen; Ju, Huangxian; Jia, Li; Bao, Lei; Yu, Jun-ShengJournal of the American Chemical Society (2013), 135 (50), 18850-18858CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Spatiotemporal control of singlet oxygen (1O2) release is a major challenge for photodynamic therapy (PDT) against cancer with high therapeutic efficacy and min. side effects. Here a selenium-rubyrin (NMe2Se4N2)-loaded nanoparticle functionalized with folate (FA) was designed and synthesized as an acidic pH-activatable targeted photosensitizer. The nanoparticles could specifically recognize cancer cells via the FA-FA receptor binding and were selectively taken up by cancer cells via receptor-mediated endocytosis to enter lysosomes, in which NMe2Se4N2 was activated to produce 1O2. The pH-controllable release of 1O2 specially damaged the lysosomes and thus killed cancer cells in a lysosome-assocd. pathway. The introduction of selenium into the rubyrin core enhanced the 1O2 generation efficiency due to the heavy atom effect, and the substitution of dimethylaminophenyl moiety at meso-position led to the pH-controllable activation of NMe2Se4N2. Under near-IR (NIR) irradn., NMe2Se4N2 possessed high singlet oxygen quantum yield (ΦΔ) at an acidic pH (ΦΔ = 0.69 at pH 5.0 at 635 nm) and could be deactivated at physiol. pH (ΦΔ = 0.06 at pH 7.4 at 635 nm). The subcellular location-confined pH-activatable photosensitization at NIR region and the cancer cell-targeting feature led to excellent capability to selectively kill cancer cells and prevent the damage to normal cells, which greatly lowered the side effects. Through i.v. injection of FA-NMe2Se4N2 nanoparticles in tumor-bearing mice, tumor elimination was obsd. after NIR irradn. This work presents a new paradigm for specific PDT against cancer and provides a new avenue for prepn. of highly efficient photosensitizers.313Tsai, H. C.; Tsai, C. H.; Lin, S. Y.; Jhang, C. R.; Chiang, Y. S.; Hsiue, G. H. Stimulated Release of Photosensitizers from Graft and Diblock Micelles for Photodynamic Therapy. Biomaterials 2012, 33, 1827– 1837, DOI: 10.1016/j.biomaterials.2011.11.014[Crossref], [PubMed], [CAS], Google Scholar313https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1ejtL7K&md5=da5136aa6bc14848a12c0f682e608ac9Stimulated release of photosensitizers from graft and diblock micelles for photodynamic therapyTsai, Hsieh-Chih; Tsai, Cheng-Hung; Lin, Shuian-Yin; Jhang, Chang-Rong; Chiang, Yung-Sheng; Hsiue, Ging-HoBiomaterials (2012), 33 (6), 1827-1837CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)To understand the effect of photosensitizer (PS) release from graft copolymer based micelles in photodynamic therapy (PDT), the two pH-sensitive and non-pH-sensitive graft copolymers, (poly(N-vinylcaprolactam)-g-poly(D,L-lactide) and poly(N-vinylcaprolactam-co-N-vinyl imidazole)-g-poly(D,L-lactide)), were synthesized and utilized for the encapsulation of protoporphyrin IX (PPIX) for in vitro and in vivo PDT studies. Photochem. internalization (PCI) was utilized to study the localization of pH- and non-pH-sensitive micelles uptake in the lysosome. After non-toxic light treatment, PPIX was found in the nucleus with pH-sensitive micelles, while PPIX was still localized in the lysosomal organism with the non-pH-sensitive micelles, as obsd. by confocal microscopy. Because the formation of singlet oxygen was obsd. for the block and graft micelles, dramatic differences in the cell viability could be ascribed to the damage occurring at the region where the PPIX was located. An in vivo study revealed that PPIX-loaded graft and diblock micelles presented prolonged blood circulation and enhanced tumor targeting ability. The PPIX released from g-CIM micelles on tumor site was further proved by ex vivo confocal image. In addn., non-pH-sensitive micelle-treated mice showed a better repression of tumor growth than PPIX-treated mice, which was likely due to the larger amt. of PS localized in the tumor region still exhibiting therapeutic effects. Finally, effective PDT-induced inhibition of tumor growth was found in pH-sensitive micelle-treated mice. This work provides insight into PS-loaded graft and diblock micelles for the PDT of tumors.314Kim, H.; Mun, S.; Choi, Y. Photosensitizer-Conjugated Polymeric Nanoparticles for Redox-Responsive Fluorescence Imaging and Photodynamic Therapy. J. Mater. Chem. B 2013, 1, 429– 431, DOI: 10.1039/C2TB00287F[Crossref], [PubMed], [CAS], Google Scholar314https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVyms7bP&md5=730e3fedd75309c0febd005cbd7cab8bPhotosensitizer-conjugated polymeric nanoparticles for redox-responsive fluorescence imaging and photodynamic therapyKim, Hyunjin; Mun, Saehun; Choi, YongdooJournal of Materials Chemistry B: Materials for Biology and Medicine (2013), 1 (4), 429-431CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)Photosensitizers conjugated with hyaluronic acid via disulfide linkers were developed for biol. activatable near-IR fluorescence imaging and photodynamic therapy. The nanoparticles prepd. from the conjugate are nonfluorescent and nonphototoxic in their native state, but become highly fluorescent and phototoxic in response to reductive agents inside cancer cells.315Wang, C.; Cheng, L.; Liu, Y.; Wang, X.; Ma, X.; Deng, Z.; Li, Y.; Liu, Z. Imaging-Guided PH-Sensitive Photodynamic Therapy Using Charge Reversible Upconversion Nanoparticles Under Near -Infrared Light. Adv. Funct. Mater. 2013, 23, 3077– 3086, DOI: 10.1002/adfm.201202992[Crossref], [CAS], Google Scholar315https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFSqu78%253D&md5=6f99f4013e5a376db12d0713dd91799eImaging-Guided pH-Sensitive Photodynamic Therapy Using Charge Reversible Upconversion Nanoparticles under Near-Infrared LightWang, Chao; Cheng, Liang; Liu, Yumeng; Wang, Xiaojing; Ma, Xinxing; Deng, Zhaoyi; Li, Yonggang; Liu, ZhuangAdvanced Functional Materials (2013), 23 (24), 3077-3086CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)Photodynamic therapy (PDT) based on upconversion nanoparticles (UCNPs) can effectively destroy cancer cells under tissue-penetrating near-IR light (NIR) light. Herein, we synthesize manganese (Mn2+)-doped UCNPs with strong red light emission at ca. 660 nm under 980 nm NIR excitation to activate Chlorin e6 (Ce6), producing singlet oxygen (1O2) to kill cancer cells. A layer-by-layer (LbL) self-assembly strategy is employed to load multiple layers of Ce6 conjugated polymers onto UCNPs via electrostatic interactions. UCNPs with two layers of Ce6 loading ([email protected]) are found to be optimal in terms of Ce6 loading and 1O2 generation. By further coating [email protected] with an outer layer of charge-reversible polymer contg. dimethylmaleic acid (DMMA) groups and polyethylene glycol (PEG) chains, we obtain a [email protected] nanocomplex, the surface of which is neg. charged and PEG coated under pH 7.4; this could be converted to have a pos. charged naked surface at pH 6.8, significantly enhancing cell internalization of nanoparticles and increasing in vitro NIR-induced PDT efficacy. We then utilize the intrinsic optical and paramagnetic properties of Mn2+-doped UCNPs for in vivo dual modal imaging, and uncover an enhanced retention of [email protected] inside the tumor after intratumoral injection, owing to the slightly acidic tumor microenvironment. Consequently, a significantly improved in vivo PDT therapeutic effect is achieved using our charge-reversible [email protected] nanoparticles. Finally, we further demonstrate the remarkably enhanced tumor-homing of these pH-responsive charge-switchable nanoparticles in comparison to a control counterpart without pH sensitivity after systemic i.v. injection. Our results suggest that UCNPs with finely designed surface coatings could serve as smart pH-responsive PDT agents promising in cancer theranostics.316Yoon, H. Y.; Koo, H.; Choi, K. Y.; Lee, S. J.; Kim, K.; Kwon, I. C.; Leary, J. F.; Park, K.; Yuk, S. H.; Park, J. H.; Choi, K. Tumor-Targeting Hyaluronic Acid Nanoparticles for Photodynamic Imaging and Therapy. Biomaterials 2012, 33, 3980– 3989, DOI: 10.1016/j.biomaterials.2012.02.016[Crossref], [PubMed], [CAS], Google Scholar316https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivFWrs7c%253D&md5=a0ccf0320f80ff13519a8e3b1643f9a6Tumor-targeting hyaluronic acid nanoparticles for photodynamic imaging and therapyYoon, Hong Yeol; Koo, Heebeom; Choi, Ki Young; Lee, So Jin; Kim, Kwangmeyung; Kwon, Ick Chan; Leary, James F.; Park, Kinam; Yuk, Soon Hong; Park, Jae Hyung; Choi, KuiwonBiomaterials (2012), 33 (15), 3980-3989CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Tumor-targeted imaging and therapy have been the challenging issue in the clin. field. Herein, we report tumor-targeting hyaluronic acid nanoparticles (HANPs) as the carrier of the hydrophobic photosensitizer, chlorin e6 (Ce6) for simultaneous photodynamic imaging and therapy. First, self-assembled HANPs were synthesized by chem. conjugation of aminated 5β-cholanic acid, polyethylene glycol (PEG), and black hole quencher3 (BHQ3) to the HA polymers. Second, Ce6 was readily loaded into the HANPs by a simple dialysis method resulting in Ce6-loaded hyaluronic acid nanoparticles (Ce6-HANPs), wherein in the loading efficiency of Ce6 was higher than 80%. The resulting Ce6-HANPs showed stable nano-structure in aq. condition and rapid uptake into tumor cells. In particular Ce6-HANPs were rapidly degraded by hyaluronidases abundant in cytosol of tumor cells, which may enable intracellular release of Ce6 at the tumor tissue. After an i.v. injection into the tumor-bearing mice, Ce6-HANPs could efficiently reach the tumor tissue via the passive targeting mechanism and specifically enter tumor cells through the receptor-mediated endocytosis based on the interactions between HA of nanoparticles and CD44, the HA receptor on the surface of tumor cells. Upon laser irradn., Ce6 which was released from the nanoparticles could generate fluorescence and singlet oxygen inside tumor cells, resulting in effective suppression of tumor growth. Overall, it was demonstrated that Ce6-HANPs could be successfully applied to in vivo photodynamic tumor imaging and therapy simultaneously.317Lee, S. J.; Koo, H.; Jeong, H.; Huh, M. S.; Choi, Y.; Jeong, S. Y.; Byun, Y.; Choi, K.; Kim, K.; Kwon, I. C. Comparative Study of Photosensitizer Loaded and Conjugated Glycol Chitosan Nanoparticles for Cancer Therapy. J. Controlled Release 2011, 152, 21– 29, DOI: 10.1016/j.jconrel.2011.03.027[Crossref], [PubMed], [CAS], Google Scholar317https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmvFyksLc%253D&md5=b8b07ec369efb73defe029216bf9dff0Comparative study of photosensitizer loaded and conjugated glycol chitosan nanoparticles for cancer therapyLee, So Jin; Koo, Heebeom; Jeong, Hayoung; Huh, Myung Sook; Choi, Yongseok; Jeong, Seo Young; Byun, Youngro; Choi, Kuiwon; Kim, Kwangmeyung; Kwon, Ick ChanJournal of Controlled Release (2011), 152 (1), 21-29CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)This study reports that tumor-targeting glycol chitosan nanoparticles with phys. loaded and chem. conjugated photosensitizers can be used in photodynamic therapy (PDT). First, the hydrophobic photosensitizer, chlorin e6 (Ce6), was phys. loaded onto the hydrophobically-modified glycol chitosan nanoparticles (HGC), which were prepd. by self-assembling amphiphilic glycol chitosan-5β-cholanic acid conjugates under aq. conditions. Second, the Ce6s were chem. conjugated to the glycol chitosan polymers, resulting in amphiphilic glycol chitosan-Ce6 conjugates that formed self-assembled nanoparticles in aq. condition. Both Ce6-loaded glycol chitosan nanoparticles (HGC-Ce6) and Ce6-conjugated chitosan nanoparticles (GC-Ce6) had similar av. diams. of 300 to 350 nm, a similar in vitro singlet oxygen generation efficacy under buffer conditions, and a rapid cellular uptake profile in the cell culture system. However, compared to GC-Ce6, HGC-Ce6 showed a burst of drug release in vitro, whereby 65% of phys. loaded drugs were rapidly released from the particles within 6.5 h in the buffer condition. When injected through the tail vein into tumor bearing mice, HGC-Ce6 did not accumulate efficiently in tumor tissue, reflecting the burst in the release of the phys. loaded drug, while GC-Ce6 showed a prolonged circulation profile and a more efficient tumor accumulation, which resulted in high therapeutic efficacy. These comparative studies with drug-loaded and drug-conjugated nanoparticles showed that the photosensitizer-conjugated glycol chitosan nanoparticles with excellent tumor targeting properties have potential for PDT in cancer treatment.318Taratula, O.; Patel, M.; Schumann, C.; Naleway, M. A.; Pang, A. J.; He, H.; Taratula, O. Phthalocyanine-Loaded Graphene Nanoplatform for Imaging-Guided Combinatorial Phototherapy. Int. J. Nanomed. 2015, 10, 2347– 2362, DOI: 10.2147/IJN.S81097[Crossref], [PubMed], [CAS], Google Scholar318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmvFCjtbc%253D&md5=b98761878a1323794932fcd7ea35b809Phthalocyanine-loaded graphene nanoplatform for imaging-guided combinatorial phototherapyTaratula, Olena; Patel, Mehulkumar; Schumann, Canan; Naleway, Michael A.; Pang, Addison J.; He, Huixin; Taratula, OlehInternational Journal of Nanomedicine (2015), 10 (), 2347-2362CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)We report a novel cancer-targeted nanomedicine platform for imaging and prospect for future treatment of unresected ovarian cancer tumors by intraoperative multimodal phototherapy. To develop the required theranostic system, novel low-oxygen graphene nanosheets were chem. modified with polypropylenimine dendrimers loaded with phthalocyanine (Pc) as a photosensitizer. Such a mol. design prevents fluorescence quenching of the Pc by graphene nanosheets, providing the possibility of fluorescence imaging. Furthermore, the developed nanoplatform was conjugated with poly(ethylene glycol), to improve biocompatibility, and with LH-releasing hormone (LHRH) peptide, for tumor-targeted delivery. Notably, a low-power near-IR (NIR) irradn. of single wavelength was used for both heat generation by the graphene nanosheets (photothermal therapy [PTT]) and for reactive oxygen species (ROS)-prodn. by Pc (photodynamic therapy [PDT]). The combinatorial phototherapy resulted in an enhanced destruction of ovarian cancer cells, with a killing efficacy of 90%-95% at low Pc and low-oxygen graphene dosages, presumably conferring cytotoxicity to the synergistic effects of generated ROS and mild hyperthermia. An animal study confirmed that Pc loaded into the nanoplatform can be employed as a NIR fluorescence agent for imaging-guided drug delivery. Hence, the newly developed Pc-graphene nanoplatform has the significant potential as an effective NIR theranostic probe for imaging and combinatorial phototherapy.319Choi, Y.; Kim, S.; Choi, M.-H.; Ryoo, S.-R.; Park, J.; Min, D.-H.; Kim, B.-S. Photodynamic Therapy: Highly Biocompatible Carbon Nanodots for Simultaneous Bioimaging and Targeted Photodynamic Therapy In Vitro and In Vivo. Adv. Funct. Mater. 2014, 24, 5774– 5774A, DOI: 10.1002/adfm.201470245[Crossref], [CAS], Google Scholar319https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1yht7zJ&md5=679e980a47d54b768ae1a7b19b957f5fPhotodynamic Therapy: Highly Biocompatible Carbon Nanodots for Simultaneous Bioimaging and Targeted Photodynamic Therapy In Vitro and In Vivo (Adv. Funct. Mater. 37/2014)Choi, Yuri; Kim, Seongchan; Choi, Myung-Ho; Ryoo, Soo-Ryoon; Park, Jongnam; Min, Dal-Hee; Kim, Byeong-SuAdvanced Functional Materials (2014), 24 (37), 5774CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)There is no expanded citation for this reference.320Koo, H.; Lee, H.; Lee, S.; Min, K. H.; Kim, M. S.; Lee, D. S.; Choi, Y.; Kwon, I. C.; Kim, K.; Jeong, S. Y. In Vivo Tumor Diagnosis and Photodynamic Therapy via Tumoral PH-Responsive Polymeric Micelles. Chem. Commun. 2010, 46, 5668– 5670, DOI: 10.1039/c0cc01413c[Crossref], [PubMed], [CAS], Google Scholar320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpsFelu7g%253D&md5=bad3e169825d5ebc92f7b399529296a3In vivo tumor diagnosis and photodynamic therapy via tumoral pH-responsive polymeric micellesKoo, Heebeom; Lee, Hyejung; Lee, Sojin; Min, Kyung Hyun; Kim, Min Sang; Lee, Doo Sung; Choi, Yongseok; Kwon, Ick Chan; Kim, Kwangmeyung; Jeong, Seo YoungChemical Communications (Cambridge, United Kingdom) (2010), 46 (31), 5668-5670CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)We report protoporphyrin IX (PpIX) encapsulated pH-responsive micelles for cancer treatment. This system showed pH-responsive micellization/demicellization transition at tumoral acidic pH and enabled in vivo tumor diagnosis and therapy simultaneously.321Lovell, J. F.; Jin, C. S.; Huynh, E.; MacDonald, T. D.; Cao, W.; Zheng, G. Enzymatic Regioselection for the Synthesis and Biodegradation of Porphysome Nanovesicles. Angew. Chem., Int. 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This enzymic screening approach and the two enzymes identified here may be useful for generating other types of isomerically pure phospholipid conjugates. Regioisomeric phospholipid conjugates can generate nanoparticles that are phys. similar, but vary greatly in how the nanoparticles biodegrade in vivo. Further research is warranted in studying the nature of enzymic biodegrdn. of nanoparticles in vivo.322Yi, X. M.; Wang, F. L.; Qin, W. J.; Yang, X. J.; Yuan, J. L. Near-Infrared Fluorescent Probes in Cancer Imaging and Therapy: An Emerging Field. Int. J. Nanomed. 2014, 9, 1347– 1365, DOI: 10.2147/IJN.S60206[Crossref], [PubMed], [CAS], Google Scholar322https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crmvFCrsw%253D%253D&md5=de91fbc9335621319c7f65aa1a0f1787Near-infrared fluorescent probes in cancer imaging and therapy: an emerging fieldYi Xiaomin; Wang Fuli; Qin Weijun; Yang Xiaojian; Yuan JianlinInternational journal of nanomedicine (2014), 9 (), 1347-65 ISSN:.Near-infrared fluorescence (NIRF) imaging is an attractive modality for early cancer detection with high sensitivity and multi-detection capability. Due to convenient modification by conjugating with moieties of interests, NIRF probes are ideal candidates for cancer targeted imaging. Additionally, the combinatory application of NIRF imaging and other imaging modalities that can delineate anatomical structures extends fluorometric determination of biomedical information. Moreover, nanoparticles loaded with NIRF dyes and anticancer agents contribute to the synergistic management of cancer, which integrates the advantage of imaging and therapeutic functions to achieve the ultimate goal of simultaneous diagnosis and treatment. Appropriate probe design with targeting moieties can retain the original properties of NIRF and pharmacokinetics. In recent years, great efforts have been made to develop new NIRF probes with better photostability and strong fluorescence emission, leading to the discovery of numerous novel NIRF probes with fine photophysical properties. Some of these probes exhibit tumoricidal activities upon light radiation, which holds great promise in photothermal therapy, photodynamic therapy, and photoimmunotherapy. This review aims to provide a timely and concise update on emerging NIRF dyes and multifunctional agents. Their potential uses as agents for cancer specific imaging, lymph node mapping, and therapeutics are included. Recent advances of NIRF dyes in clinical use are also summarized.323Hu, J. J.; Liu, L. H.; Li, Z. Y.; Zhuo, R. X.; Zhang, X. Z. MMP-Responsive Theranostic Nanoplatform Based on Mesoporous Silica Nanoparticles for Tumor Imaging and Targeted Drug Delivery. J. Mater. Chem. B 2016, 4, 1932– 1940, DOI: 10.1039/C5TB02490K[Crossref], [PubMed], [CAS], Google Scholar323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XisFWnuro%253D&md5=ff211b6f856f92c0d4f4d14694b20b31MMP-responsive theranostic nanoplatform based on mesoporous silica nanoparticles for tumor imaging and targeted drug deliveryHu, Jing-Jing; Liu, Li-Han; Li, Ze-Yong; Zhuo, Ren-Xi; Zhang, Xian-ZhengJournal of Materials Chemistry B: Materials for Biology and Medicine (2016), 4 (11), 1932-1940CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)In this paper, we report on an intelligent mesoporous silica-based multifunctional theranostic nanoplatform (designated as MMTNP) for tumor imaging as well as controlled drug release. This theranostic nanoplatform consists of MCM-41 typical mesoporous silica nanoparticles (MSNs) as a hydrophobic drug carrier, matrix metalloprotease-2 (MMP-2) activated fluorescence imaging peptides on the surface of MSNs served as diagnostic probes as well as enzyme-responsive nanovalves blocking the pores, and cRGD peptides further functionalized on the surface of MSNs for tumor targeting. In the absence of MMP-2 conditions, the proximity between the fluorescent dye 5(6)-carboxytetramethylrhodamine hydrochloride (TAMRA) and the quencher 4,4-dimethylamino-azobenzene-4'-carboxylic acid (Dabcyl) on the surface of MSNs resulted in no fluorescence. When the drug loaded nanoplatform arrived at tumor tissue with overexpressed MMP-2, the fluorescence of TAMRA became recovered efficiently due to the hydrolysis of the MMP-2 sensitive peptide substrate, realizing tumor imaging and triggering drug release. In addn., the further introduced cRGD peptide significantly enhanced the targeting efficiency through receptor-mediated endocytosis in tumor cells.324Kim, J.; Tung, C. H.; Choi, Y. Smart Dual-Functional Warhead for Folate Receptor-Specific Activatable Imaging and Photodynamic Therapy. Chem. Commun. 2014, 50, 10600– 10603, DOI: 10.1039/C4CC04166F[Crossref], [PubMed], [CAS], Google Scholar324https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1aiurrE&md5=28ffa77e9f59b3e27676c30fa53eff11Smart dual-functional warhead for folate receptor-specific activatable imaging and photodynamic therapyKim, Jisu; Tung, Ching-Hsuan; Choi, YongdooChemical Communications (Cambridge, United Kingdom) (2014), 50 (73), 10600-10603CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A smart dual-targeted theranostic agent becomes highly fluorescent and phototoxic only when its linker is cleaved by tumor-assocd. lysosomal enzyme cathepsin B after internalization into folate receptor-pos. cancer cells.325Haedicke, K.; Kozlova, D.; Gräfe, S.; Teichgräber, U.; Epple, M.; Hilger, I. Multifunctional Calcium Phosphate Nanoparticles for Combining Near-Infrared Fluorescence Imaging and Photodynamic Therapy. Acta Biomater. 2015, 14, 197– 207, DOI: 10.1016/j.actbio.2014.12.009[Crossref], [PubMed], [CAS], Google Scholar325https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVCls7k%253D&md5=5e6b7752c7e07f74ec8b48f00660467eMultifunctional calcium phosphate nanoparticles for combining near-infrared fluorescence imaging and photodynamic therapyHaedicke, Katja; Kozlova, Diana; Graefe, Susanna; Teichgraeber, Ulf; Epple, Matthias; Hilger, IngridActa Biomaterialia (2015), 14 (), 197-207CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)Photodynamic therapy (PDT) of tumors causes skin photosensitivity as a result of unspecific accumulation behavior of the photosensitizers. PDT of tumors was improved by calcium phosphate nanoparticles conjugated with (i) Temoporfin as a photosensitizer, (ii) the RGDfK peptide for favored tumor targeting and (iii) the fluorescent dye mol. DY682-NHS for enabling near-IR fluorescence (NIRF) optical imaging in vivo. The nanoparticles were characterized with regard to size, spectroscopic properties and uptake into CAL-27 cells. The nanoparticles had a hydrodynamic diam. of approx. 200 nm and a zeta potential of around +22 mV. Their biodistribution at 24 h after injection was investigated via NIRF optical imaging. After treating tumor-bearing CAL-27 mice with nanoparticle-PDT, the therapeutic efficacy was assessed by a fluorescent DY-734-annexin V probe at 2 days and 2 wk after treatment to detect apoptosis. Addnl., the contrast agent IRDye 800CW RGD was used to assess tumor vascularization (up to 4 wk after PDT). After nanoparticle-PDT in mice, apoptosis in the tumor was detected after 2 days. Decreases in tumor vascularization and tumor vol. were detected in the next few days. Calcium phosphate nanoparticles can be used as multifunctional tools for NIRF optical imaging, PDT and tumor targeting as they exhibited a high therapeutic efficacy, being capable of inducing apoptosis and destroying tumor vascularization.326Schneider, R.; Schmitt, F.; Frochot, C.; Fort, Y.; Lourette, N.; Guillemin, F.; Müller, J. F.; Barberi-Heyob, M. Design, Synthesis, and Biological Evaluation of Folic Acid Targeted Tetraphenylporphyrin as Novel Photosensitizers for Selective Photodynamic Therapy. Bioorg. Med. Chem. 2005, 13, 2799– 2808, DOI: 10.1016/j.bmc.2005.02.025[Crossref], [PubMed], [CAS], Google Scholar326https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXisVCgsLg%253D&md5=ca3fa28aeb2547a601c38ab8da4c7366Design, synthesis, and biological evaluation of folic acid targeted tetraphenylporphyrin as novel photosensitizers for selective photodynamic therapySchneider, Raphael; Schmitt, Frederic; Frochot, Celine; Fort, Yves; Lourette, Natacha; Guillemin, Francois; Mueller, Jean-Francois; Barberi-Heyob, MurielBioorganic & Medicinal Chemistry (2005), 13 (8), 2799-2808CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)Photodynamic therapy (PDT) is a cancer treatment involving systemic administration of a tumor-localizing photosensitizer; this, when activated by the appropriate light wavelength, interacts with mol. oxygen to form a toxic, short-lived species known as singlet oxygen, which is thought to mediate cellular death. Targeted PDT offers the opportunity of enhancing photodynamic efficiency by directly targeting diseased cells and tissues. Two new conjugates of three components, folic acid/hexane-1,6-diamine/4-carboxyphenylporphyrine 1 and folic acid/2,2'-(ethylenedioxy)-bis-ethylamine/4-carboxyphenylporphyrine 2 were synthesized. The conjugates were characterized by 1H NMR, MALDI, UV-visible spectroscopy, and fluorescence quantum yield. The targeted delivery of these photoactive compds. to KB nasopharyngeal cell line, which is one of the numerous tumor cell types that overexpress folate receptors was studied. It was found that after 24 h incubation, conjugates 1 and 2 cellular uptake was on av. 7-fold higher than tetraphenylporphyrin (TPP) used as ref. and that 1 and 2 cellular uptake kinetics increased steadily over the 24 h period, suggesting an active transport via receptor-mediated endocytosis. In corresponding results, conjugates 1 and 2 accumulation displayed a redn. of 70% in the presence of a competitive concn. of folic acid. Survival measurements demonstrated that KB cells were significantly more sensitive to conjugated porphyrins-mediated PDT. Under the same exptl. conditions and the same photosensitizer concn., TPP displayed no photocytotoxicity while conjugates 1 and 2 showed photodynamic activity with light dose values yielding 50% growth inhibition of 22.6 and 6.7 J/cm2, resp.327Wang, F.; Chen, X.; Zhao, Z.; Tang, S.; Huang, X.; Lin, C.; Cai, C.; Zheng, N. Synthesis of Magnetic, Fluorescent and Mesoporous Core-Shell-Structured Nanoparticles for Imaging, Targeting and Photodynamic Therapy. J. Mater. Chem. 2011, 21, 11244– 11252, DOI: 10.1039/c1jm10329f[Crossref], [CAS], Google Scholar327https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptVyns7c%253D&md5=e7b815671445fd55612c38bb43422e22Synthesis of magnetic, fluorescent and mesoporous core-shell-structured nanoparticles for imaging, targeting and photodynamic therapyWang, Fang; Chen, Xiao-Lan; Zhao, Zeng-Xia; Tang, Shao-Heng; Huang, Xiao-Qing; Lin, Cheng-Hong; Cai, Cong-bo; Zheng, Nan-FengJournal of Materials Chemistry (2011), 21 (30), 11244-11252CODEN: JMACEP; ISSN:0959-9428. (Royal Society of Chemistry)A synthetic method to prep. novel multifunctional core-shell-structured mesoporous silica nanoparticles for simultaneous magnetic resonance (MR) and fluorescence imaging, cell targeting and photosensitization treatment has been developed. Superparamagnetic magnetite nanoparticles and fluorescent dyes are co-encapsulated inside nonporous silica nanoparticles as the core to provide dual-imaging capabilities (MR and optical). The photosensitizer mols., tetra-substituted carboxyl aluminum phthalocyanine (AlC4Pc), are covalently linked to the mesoporous silica shell and exhibit excellent photo-oxidn. efficiency. The surface modification of the core-shell silica nanoparticles with folic acid enhances the delivery of photosensitizers to the targeting cancer cells that overexpress the folate receptor, and thereby decreases their toxicity to the surrounding normal tissues. These unique advantages make the prepd. multifunctional core-shell silica nanoparticles promising for cancer diagnosis and therapy.328Kenanova, V.; Wu, A. M. Tailoring Antibodies for Radionuclide Delivery. Expert Opin. Drug Delivery 2006, 3, 53– 70, DOI: 10.1517/17425247.3.1.53[Crossref], [PubMed], [CAS], Google Scholar328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtlCms7zI&md5=72b11b620ba7250589ef7fa8d0b1d870Tailoring antibodies for radionuclide deliveryKenanova, Vania; Wu, Anna M.Expert Opinion on Drug Delivery (2006), 3 (1), 53-70CODEN: EODDAW; ISSN:1742-5247. (Ashley Publications Ltd.)A review. Therapeutic antibodies are well established as an important class of drugs in modern medicine. The exquisite specificity and affinity for a specific target offered by antibodies has also encouraged their development as delivery vehicles for agents such as radionuclides to target tissues, for radioimmunoimaging and radioimmunotherapy. Specifically, in nuclear medicine, radionuclide-conjugated antibody mols. make it possible to image diseased loci with greater sensitivity than other imaging modalities such as magnetic resonance imaging. Furthermore, two radionuclide-conjugated antibodies have recently been approved for the therapy of non-Hodgkin's lymphoma. However, optimal implementation of antibodies has been limited by the extended circulation persistence that is characteristic of native antibodies, which is responsible for increased background activity in radioimmunoimaging applications and dose-related normal organ toxicities in radioimmunotherapy. In this article the current status of radiolabeled intact antibodies is reviewed, focusing on strategies to improve their pharmacokinetic properties to suit a desired application. Examples from the literature that represent different approaches to accomplishing this task in terms of their successes as well as limitations, and perspectives for the future are discussed.329Vieira, P.; Rajewsky, K. The Half-Lives of Serum Immunoglobulins in Adult Mice. Eur. J. Immunol. 1988, 18, 313– 316, DOI: 10.1002/eji.1830180221[Crossref], [PubMed], [CAS], Google Scholar329https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXhvVCrs7Y%253D&md5=2c644134b8964794b3391b7c796f8537The half-lives of serum immunoglobulins in adult miceVieira, Paulo; Rajewsky, KlausEuropean Journal of Immunology (1988), 18 (2), 313-16CODEN: EJIMAF; ISSN:0014-2980.The half-lives were detd. of several sets of murine monoclonal antibodies spanning all Ig isotypes in the serum. The antibodies in each set possess the same V region. With this approach, the differences in half-life obsd. between the different isotypes are independent of the V region carried by the monoclonal antibodies and therefore must relate to each other in the same way as the half-lives of each class of serum Igs. The half-life of a monoclonal antibody of the γ2a isotype is identical to the av. half-life of serum IgG2a as previously detd. (6-8 days). Therefore, the half-lives detd. with monoclonal antibodies possessing the same V region represent the half-life of the serum Igs. In this way, the half-life of IgM was calcd. to be 2 days, IgG3 and IgG1 was 6-8 days, and IgG2b was 4-6 days. IgE has a half-life of 12 h. A polymeric form of IgA was eliminated from the serum with a half-life of 17-22 h.330Decristoforo, C.; Pickett, R. D.; Verbruggen, A. Feasibility and Availability of 68Ga-Labelled Peptides. Eur. J. Nucl. Med. Mol. Imaging 2012, 39, 31– 40, DOI: 10.1007/s00259-011-1988-5[Crossref], [PubMed], [CAS], Google Scholar330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xkt1CktLg%253D&md5=2b0b68682a998710c9efb7c87515e41bFeasibility and availability of 68Ga-labelled peptidesDecristoforo, Clemens; Pickett, Roger D.; Verbruggen, AlfonsEuropean Journal of Nuclear Medicine and Molecular Imaging (2012), 39 (Suppl.1), 31-40CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. 68Ga has attracted tremendous interest as a radionuclide for PET based on its suitable half-life of 68 min, high positron emission yield and ready availability from 68Ge/68Ga generators, making it independent of cyclotron prodn. 68Ga-labeled DOTA-conjugated somatostatin analogs, including DOTA-TOC, DOTA-TATE and DOTA-NOC, have driven the development of technologies to provide such radiopharmaceuticals for clin. applications mainly in the diagnosis of somatostatin receptor-expressing tumors. We summarize the issues detg. the feasibility and availability of 68Ga-labeled peptides, including generator technol., 68Ga generator eluate postprocessing methods, radiolabelling, automation and peptide developments, and also quality assurance and regulatory aspects. 68Ge/68Ga generators based on SnO2, TiO2 or org. matrixes are today routinely supplied to nuclear medicine departments, and a variety of automated systems for postprocessing and radiolabelling have been developed. New developments include improved chelators for 68Ga that could open new ways to utilize this technol. Challenges and limitations in the on-site prepn. and use of 68Ga-labeled peptides outside the marketing authorization track are also discussed.331Liang, B.; Shao, W.; Zhu, C.; Wen, G.; Yue, X.; Wang, R.; Quan, J.; Du, J.; Bu, X. Mitochondria-Targeted Approach: Remarkably Enhanced Cellular Bioactivities of TPP2a as Selective Inhibitor and Probe toward TrxR. ACS Chem. Biol. 2016, 11, 425– 434, DOI: 10.1021/acschembio.5b00708[ACS Full Text], [CAS], Google Scholar331https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVCks7c%253D&md5=e4daaa0034ea25288d022bd8ee16996fMitochondria-Targeted Approach: Remarkably Enhanced Cellular Bioactivities of TPP2a as Selective Inhibitor and Probe toward TrxRLiang, Baoxia; Shao, Weiyan; Zhu, Cuige; Wen, Gesi; Yue, Xin; Wang, Ruimin; Quan, Junmin; Du, Jun; Bu, XianzhangACS Chemical Biology (2016), 11 (2), 425-434CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)A mitochondria-targeted approach was developed to increase the cellular bioactivities of thioredoxin reductase (TrxR) inhibitors. By being conjugated with a triphenylphosphine (TPP) motif to a previously found TrxR inhibitor I (R = H), the resulted compd. TPP2a [I; R = (CH2)10P+Ph3 Br-] can target subcellular mitochondria and efficiently inhibit cellular TrxR, leading to remarkably increased cellular ROS level and mitochondrial apoptosis of HeLa cancer cells. The cellular bioactivities of TPP2a, including its cytotoxicity against a panel of cancer cell lines, dramatically elevated compared with its parental compd. I (R = H). The selectively and covalently interaction of TPP2a with subcellular mitochondrial TrxR was validated by fluorescent microscopy. Moreover, a nonspecific signal quenching coupled strategy was proposed based on the environmentally sensitive fluorescence of TPP2a, which makes it possible to label TrxR by removing the nonspecific backgrounds caused by TPP2a under complex biosettings such as cellular lysates and living cells, implicating a potential of TPP2a for TrxR-specific labeling.332Isabel, M.; Prata, M. Gallium-68: A New Trend in PET Radiopharmacy. Curr. Radiopharm. 2012, 5, 142– 149, DOI: 10.2174/1874471011205020142333Roesch, F. Maturation of a Key Resource – The Germanium-68/Gallium-68 Generator: Development and New Insights. Curr. Radiopharm. 2012, 5, 202– 211, DOI: 10.2174/1874471011205030202[Crossref], [PubMed], [CAS], Google Scholar333https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtF2jt77N&md5=55b95e6a5982d3243c6225b18ec751f4Maturation of a key resource - the germanium-68/gallium-68 generator: development and new insightsRoesch, F.Current Radiopharmaceuticals (2012), 5 (3), 202-211CODEN: CRUAC7; ISSN:1874-4710. (Bentham Science Publishers Ltd.)A review. 68Ge/68Ga radionuclide generators have been investigated for almost fifty years, since the cyclotronindependent availability of positron emitting 68Ga via the 68Ge/68Ga system had always attracted researches working in basic nuclear chem. as well as radiopharmaceutical chem. However, it took decades and generations of research (and researchers) to finally reach a level of 68Ge/68Ga radionuclide generator designs adequate to the modern requirements of radiometal labeling chem. Nevertheless, most of the existing com. generator systems address aspects of 68Ge breakthrough and safe synthesis of 68Ga radiopharmaceuticals by adopting eluate post-processing technologies. Among the strategies to purify 68Ga eluates, the cation exchange based version is relevant in terms of purifn. efficiency. In addn., it offers more options towards further developments of 68Ga radiopharmaceuticals. Today, one may expect that the 68Ge/68Ga radionuclide generator systems could contribute to the clin. impact of nuclear medicine diagnoses for PET similar to the established 99Mo/99mTc generator system for SPECT. The exciting perspective for the 68Ge/68Ga radionuclide generator system, in turn, asks for systematic chem., radiochem., technol. and radiopharmaceutical efforts, to guarantee reliable, highly-efficient and medically approved 68Ge/68Ga generator systems.334Gaedicke, S.; Braun, F.; Prasad, S.; Machein, M.; Firat, E.; Hettich, M.; Gudihal, R.; Zhu, X.; Klingner, K.; Schüler, J.; Herold-Mende, C. C.; Grosu, A. L.; Behe, M.; Weber, W.; Mäcke, H.; Niedermann, G. Noninvasive Positron Emission Tomography and Fluorescence Imaging of CD133+ Tumor Stem Cells. Proc. Natl. Acad. Sci. U. S. 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The AC133 epitope of CD133 currently is one of the best-characterized tumor stem cell markers for many intra- and extracranial tumor entities. Here we demonstrate the successful noninvasive detection of AC133+ tumor stem cells by PET and near-IR fluorescence mol. tomog. in s.c. and orthotopic glioma xenografts using antibody-based tracers. Particularly, microPET with 64Cu-NOTA-AC133 mAb yielded high-quality images with outstanding tumor-to-background contrast, clearly delineating s.c. tumor stem cell-derived xenografts from surrounding tissues. Intracerebral tumors as small as 2-3 mm also were clearly discernible, and the microPET images reflected the invasive growth pattern of orthotopic cancer stem cell-derived tumors with low d. of AC133+ cells. These data provide a basis for further preclin. and clin. use of the developed tracers for high-sensitivity and high-resoln. monitoring of AC133+ tumor stem cells.335Cho, Y. W.; Park, S. A.; Han, T. H.; Son, D. H.; Park, J. S.; Oh, S. J.; Moon, D. H.; Cho, K. J.; Ahn, C. H.; Byun, Y.; Kim, I. S.; Kwon, I. C.; Kim, S. Y. Vivo Tumor Targeting and Radionuclide Imaging with Self-Assembled Nanoparticles: Mechanisms, Key Factors, and Their Implications. Biomaterials 2007, 28, 1236– 1247, DOI: 10.1016/j.biomaterials.2006.10.002[Crossref], [PubMed], [CAS], Google Scholar335https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28npvFyrtw%253D%253D&md5=9ad41e501a48abb893e83056eca0ba5eIn vivo tumor targeting and radionuclide imaging with self-assembled nanoparticles: mechanisms, key factors, and their implicationsCho Yong Woo; Park Soo Ah; Han Tae Hee; Son Dai Hyun; Park Ji Sun; Oh Seung Jun; Moon Dae Hyuk; Cho Kyung-Ja; Ahn Cheol-Hee; Byun Youngro; Kim In-San; Kwon Ick Chan; Kim Sang YoonBiomaterials (2007), 28 (6), 1236-47 ISSN:0142-9612.The development of more selective delivery systems for cancer diagnosis and chemotherapy is one of the most important goals of current anticancer research. The purpose of this study is to evaluate various self-assembled nanoparticles as candidates to shuttle radionuclide and/or drugs into tumors and to investigate the mechanisms underlying the tumor targeting with self-assembled nanoparticles. By combining different hydrophobic moieties and hydrophilic polymer backbones, various self-assembled nanoparticles were prepared, and their in vivo distributions in tumor-bearing mice were studied by radionuclide imaging. One type of nanoparticles (fluorescein isothiocyanate-conjugated glycol chitosan (FGC) nanoparticles) exhibited highly selective tumoral localization. Scintigraphic images obtained 1 day after the intravenous injection of FGC nanoparticles clearly delineated the tumor against adjacent tissues. The mechanisms underlying the tumor targeting with self-assembled nanoparticles were investigated in terms of the physicochemical properties of nanoparticles and tumor microenvironments. FGC nanoparticles were preferentially localized in perivascular regions, implying their extravasation to tumors through the hyperpermeable tumor vasculature. The magnitude and pattern of tumoral distribution of self-assembled nanoparticles were influenced by several key factors--(i) in vivo colloidal stability: nanoparticles should maintain their intact nanostructures in vivo for a long period of time, (ii) particle size, (iii) intracellular uptake of nanoparticle: fast cellular uptake greatly facilitates the tumor targeting, (iv) tumor angiogenesis: pathological angiogenesis permits access of nanoparticles to tumors. We believe that this work can provide insight for the engineering of nanoparticles and be extended to cancer therapy and diagnosis, so as to deliver multiple therapeutic agents and imaging probes at high local concentrations.336Mitra, A.; Nan, A.; Line, B.; Ghandehari, H. Nanocarriers for Nuclear Imaging and Radiotherapy of Cancer. Curr. Pharm. Des. 2006, 12, 4729– 4749, DOI: 10.2174/138161206779026317[Crossref], [PubMed], [CAS], Google Scholar336https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsFCntw%253D%253D&md5=f09fa5d43f3bb98949d5fe6967a1fe12Nanocarriers for nuclear imaging and radiotherapy of cancerMitra, Amitava; Nan, Anjan; Line, Bruce R.; Ghandehari, HamidrezaCurrent Pharmaceutical Design (2006), 12 (36), 4729-4749CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)A review. Several nanoscale carriers (nanoparticles, liposomes, water-sol. polymers, micelles and dendrimers) have been developed for targeted delivery of cancer diagnostic and therapeutic agents. These carriers can selectively target cancer sites and carry large payloads, thereby improving cancer detection and therapy effectiveness. Further, the combination of newer nuclear imaging techniques providing high sensitivity and spatial resoln. such as dual modality imaging with positron emission tomog./computed tomog. and use of nanoscale devices to carry diagnostic and therapeutic radionuclides with high target specificity can enable more accurate detection, staging and therapy planning of cancer. The successful clin. applications of radiolabeled monoclonal antibodies for cancer detection and therapy bode well for the future of nanoscale carrier systems in clin. oncol. Several radiolabeled multifunctional nanocarriers have been effective in detecting and treating cancer in animal models. Nonetheless, further preclin., clin. and long-term toxicity studies will be required to translate this technol. to the care of patients with cancer. The objective of this review is to present a brief but comprehensive overview of the various nuclear imaging techniques and the use of nanocarriers to deliver radionuclides for the diagnosis and therapy of cancer.337Yamamoto, F.; Yamahara, R.; Makino, A.; Kurihara, K.; Tsukada, H.; Hara, E.; Hara, I.; Kizaka-Kondoh, S.; Ohkubo, Y.; Ozeki, E.; Kimura, S. Radiosynthesis and Initial Evaluation of 18F Labeled Nanocarrier Composed of Poly(L-Lactic Acid)-Block-Poly(Sarcosine) Amphiphilic Polydepsipeptide. Nucl. Med. Biol. 2013, 40, 387– 394, DOI: 10.1016/j.nucmedbio.2012.12.008[Crossref], [PubMed], [CAS], Google Scholar337https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlahtbo%253D&md5=4b4daf1469bf6c476c61fee355f009f2Radiosynthesis and initial evaluation of 18F labeled nanocarrier composed of poly(L-lactic acid)-block-poly(sarcosine) amphiphilic polydepsipeptideYamamoto, Fumihiko; Yamahara, Ryo; Makino, Akira; Kurihara, Kensuke; Tsukada, Hideo; Hara, Eri; Hara, Isao; Kizaka-Kondoh, Shinae; Ohkubo, Yasuhito; Ozeki, Eiichi; Kimura, ShunsakuNuclear Medicine and Biology (2013), 40 (3), 387-394CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)With the aim of developing radiotracers for in vivo positron emission tomog. (PET) imaging of solid tumors based on the enhanced permeability and retention effect of nanocarriers, we have developed a polymer micelle named "Lactosome", which is composed of the amphiphilic polydepsipeptide, poly(L-lactic acid)-block-poly(sarcosine). This paper describes and evaluates the initial evaluation of the 18F-labeled Lactosome as a novel contrast agent for the tumor PET imaging technique carried out. 18F-labeled Lactosomes were prepd. by a film hydration method under sonication in water at 50 °C from a mixt. of 4-[18F]fluoro-benzoyl poly-L-lactic acid (18F-BzPLLA30) and the amphiphilic polydepsipeptide. For biodistribution studies, BALB/cA Jcl-nu/nu mice bearing HeLa cells in the femur region were used. We took both PET and near-IR fluorescence (NIRF) images of tumor bearing mice after co-injection of 18F-labeled Lactosome and NIRF-labeled Lactosome. 18F-labeled Lactosomes were prepd. at good yields (222-420 MBq) and more than 99% of 18F-BzPLLA30 was incorporated into 18F-labeled Lactosome. The radioactivity of 18F-labeled Lactosome was found to be stable and maintained at high level for up to 6 h after injection into the blood stream. Tumor uptake increased gradually after the injection. The uptake ratio of tumor/muscle was 2.7 at 6 h from the time of injection. Tumor PET imaging with 18F-labeled Lactosome was as capable as tumor NIRF imaging with NIRF-labeled Lactosome. Tumor PET imaging using Lactosome as a nanocarrier may be therefore a potential candidate for a facile and general solid tumor imaging technique.338Jerabek, P. A.; Patrick, T. B.; Kilbourn, M. R.; Dischino, D. D.; Welch, M. J. Synthesis and Biodistribution of 18F-Labeled Fluoronitroimidazoles: Potential in Vivo Markers of Hypoxic Tissue. Int. J. Radiat. Appl. Instrumentation. 1986, 37, 599– 605, DOI: 10.1016/0883-2889(86)90079-1[Crossref], [CAS], Google Scholar338https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2s%252Fjt12lsw%253D%253D&md5=5b8bf557eec0bf94f118772f48940015Synthesis and biodistribution of 18F-labeled fluoronitroimidazoles: potential in vivo markers of hypoxic tissueJerabek P A; Patrick T B; Kilbourn M R; Dischino D D; Welch M JInternational journal of radiation applications and instrumentation. Part A, Applied radiation and isotopes (1986), 37 (7), 599-605 ISSN:0883-2889.Three 18F labeled fluoronitroimidazoles have been prepared as potential in vivo markers of hypoxic cells in tumors, and ischemic areas of the heart and brain. 1-(2-Nitroimidazolyl)-3-[18F]fluoro-2-hydroxypropanol (18F]fluoro-normethoxymisonidazole) 4, 1-(2-[18F]fluoroethyl)-2-nitroimidazole 7, and 1-(2-[18F]-fluoroethyl)-2-methyl-5-nitroimidazole ([18F]fluoro-norhydroxymetronidazole) 10 were prepared in average radiochemical yields of less than 1%, 23% and 15-43% (8% at the no carrier-added level) respectively at end-of-synthesis. The in vivo biodistribution in rats was determined for each of the 18F labeled fluoronitroimidazoles. At 1 and 3 h after administration, the tissue distribution of each of the 18F labeled nitroimidzaoles was quite uniform and consistent with that of nitroimidazoles previously studied. These results suggest the need for a suitable animal model to evaluate their potential as in vivo markers of hypoxic tissue in the brain.339Grierson, J. R.; Link, J. M.; Mathis, C. A.; Rasey, J. S.; Krohn, K. A. A Radiosynthesis of Fluorine-18 Fluoromisonidazole. J. Labelled Compd. Radiopharm. 1989, 30, 343– 350, DOI: 10.1002/jlcr.2580260104340Lopci, E.; Grassi, I.; Chiti, A.; Nanni, C.; Cicoria, G.; Toschi, L.; Fonti, C.; Lodi, F.; Mattioli, S.; Fanti, S. Pet Radiopharmaceuticals for Imaging of Tumor Hypoxia: A Review of the Evidence. Am. J. Nucl. Med. Mol. Imaging 2014, 4, 365– 384[PubMed], [CAS], Google Scholar340https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1egtLrI&md5=c7b7de8f5e17092cb361bb4b51173474PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidenceLopci, Egesta; Grassi, Ilaria; Chiti, Arturo; Nanni, Cristina; Cicoria, Gianfranco; Toschi, Luca; Fonti, Cristina; Lodi, Filippo; Mattioli, Sandro; Fanti, StefanoAmerican Journal of Nuclear Medicine and Molecular Imaging (2014), 4 (4), 365-384, 20 pp.CODEN: AJNMAU; ISSN:2160-8407. (e-Century Publishing Corp.)A review. Hypoxia is a pathol. condition arising in living tissues when oxygen supply does not adequately cover the cellular metabolic demand. Detection of this phenomenon in tumors is of the utmost clin. relevance because tumor aggressiveness, metastatic spread, failure to achieve tumor control, increased rate of recurrence, and ultimate poor outcome are all assocd. with hypoxia. Consequently, in recent decades there has been increasing interest in developing methods for measurement of oxygen levels in tumors. Among the image-based modalities for hypoxia assessment, positron emission tomog. (PET) is one of the most extensively investigated based on the various advantages it offers, i.e., broad range of radiopharmaceuticals, good intrinsic resoln., three-dimensional tumor representation, possibility of semiquantification/quantification of the amt. of hypoxic tumor burden, overall patient friendliness, and ease of repetition. Compared with the other non-invasive techniques, the biggest advantage of PET imaging is that it offers the highest specificity for detection of hypoxic tissue. Starting with the 2-nitroimidazole family of compds. in the early 1980s, a great no. of PET tracers have been developed for the identification of hypoxia in living tissue and solid tumors. This paper provides an overview of the principal PET tracers applied in cancer imaging of hypoxia and discusses in detail their advantages and pitfalls.341Bourgeois, M.; Rajerison, H.; Guerard, F.; Mougin-Degraef, M.; Barbet, J.; Michel, N.; Cherel, M.; Faivre-Chauvet, A. Contribution of [64Cu]-ATSM PET in Molecular Imaging of Tumour Hypoxia Compared to Classical [18F] - MISO - A Selected Review. Nucl. Med. Rev. 2011, 14, 90– 95, DOI: 10.5603/NMR.2011.00022[Crossref], [PubMed], [CAS], Google Scholar341https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC387itVSmuw%253D%253D&md5=411baf3264eedd5abc229b864a92f424Contribution of [64Cu]-ATSM PET in molecular imaging of tumour hypoxia compared to classical [18F]-MISO--a selected reviewBourgeois Mickael; Rajerison Holisoa; Guerard Francois; Mougin-Degraef Marie; Barbet Jacques; Michel Nathalie; Cherel Michel; Faivre-Chauvet AlainNuclear medicine review. Central & Eastern Europe (2011), 14 (2), 90-5 ISSN:.During the carcinogenesis process, tumour cells often have a more rapid proliferation potential than cells that participate in blood capillary formation by neoangiogenesis. As a consequence of the poorly organized vasculature of various solid tumours, a limited oxygen delivery is observed. This hypoxic mechanism frequently occurs in solid cancers and can lead to therapeutic resistance. The present selected literature review is focused on the comparison of two positron emitting radiopharmaceuticals agents, which are currently leaders in tumour hypoxia imaging by PET. {18F}-fluoromisonidazole (=FMISO) is most commonly used as an investigational PET agent with an investigational new drug exemption from the FDA, while {64Cu}-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) has been presented as an alternative radiopharmaceutical not yet readily available. The comparison of these two radiopharmaceutical agents is particularly focused on isotope properties, radiopharmaceutical labelling process, pharmacological mechanisms, dosimetry data in patients, and clinical results in terms of image contrast. PET imaging has demonstrated a good efficacy in tumour hypoxia imaging with both FMISO and Cu-ATSM, but FMISO has presented too slow an in vivo accumulation and a weak image contrast of the hypoxia area. Despite a less favourable dosimetry, 64Cu-ATSM appears superior in terms of imaging performance, calling for industrial and clinical development of this innovative radiopharmaceutical.342Hoigebazar, L.; Jeong, J. M. Hypoxia Imaging Agents Labeled with Positron Emitters. Recent Results Cancer Res. 2013, 194, 285– 299, DOI: 10.1007/978-3-642-27994-2_15[Crossref], [PubMed], [CAS], Google Scholar342https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXltVehtLY%253D&md5=4627e341d2501557758eddba21b6cc32Hypoxia Imaging Agents Labeled with Positron EmittersHoigebazar, Lathika; Jeong, Jae MinRecent Results in Cancer Research (2013), 194 (Theranostics, Gallium-68, and Other Radionuclides), 285-299CODEN: RRCRBU; ISSN:0080-0015. (Springer GmbH)A review. Imaging hypoxia using positron emission tomog. (PET) is of great importance for therapy of cancer. [18 F]Fluoromisonidazole (FMISO) was the first PET agent for hypoxia imaging, and various radiolabeled nitroimidazole derivs. such as [18 F]fluoroerythronitroimidazole (FETNIM), [18 F]1-α- d -(2-deoxy-2-fluoroarabinofuranosyl)-2-nitroimidazole (FAZA), [18 F]2-(2-nitro-1 H -imidazol-1-yl)- N -(2,2,3,3,3-pentafluoropropyl) acetamide (EF-5), and [18 F]fluoroetanidazole (FETA) have been developed successively. To overcome the high cost of cyclotron installation, 68 Ga-labeled nitroimidazole derivs. also have been developed. Another important hypoxia imaging agent is 64 Cu-diacetyl-bis( N 4 -methylthiosemicarbazone) (64 Cu-ATSM), which can distribute in cancer tissue rapidly due to high lipophilicity. However, its application is limited due to high cost of radionuclide prodn. Although various hypoxia imaging agents have been reported and tested, hypoxia PET images still have to be improved, because of the low blood flow in hypoxic tissues and resulting low uptake of the agents.343Takasawa, M.; Moustafa, R. R.; Baron, J. C. Applications of Nitroimidazole in Vivo Hypoxia Imaging in Ischemic Stroke. Stroke 2008, 39, 1629– 1637, DOI: 10.1161/STROKEAHA.107.485938[Crossref], [PubMed], [CAS], Google Scholar343https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkvVeit7g%253D&md5=869d47fe812ae6e763103df84e0f9e9cApplications of Nitroimidazole In Vivo Hypoxia Imaging in Ischemic StrokeTakasawa, Masashi; Moustafa, Ramez Reda; Baron, Jean-ClaudeStroke (2008), 39 (5), 1629-1637CODEN: SJCCA7; ISSN:0039-2499. (Lippincott Williams & Wilkins)A review. Background and Purpose: Nitroimidazole imaging is a promising contender for noninvasive in vivo mapping of brain hypoxia after stroke. However, there is a dearth of knowledge about the behavior of these compds. in the various pathophysiol. situations encountered in ischemic stroke. In this article we report the findings from a systematic review of the literature on the use of the nitroimidazoles to map hypoxia after stroke. Summary of Review: We describe the characteristics of nitroimidazoles as imaging tracers, their pharmacol., and results of both animal and clin. studies during and after focal cerebral ischemia. Findings in brain tumors are also presented to the extent that they enlighten results in stroke. Early results from application of kinetic modeling for quant. measurement of tracer binding are briefly discussed. Conclusions: Based on this literature review, nitroimidazole hypoxia imaging agents are of considerable interest in stroke because they appear, both in animal models and in humans, to specifically detect the severely hypoxic viable tissue, but not the reperfused nor the necrotic tissue. To fully realize this potential in stroke, however, formal validation by concurrent measurement of tissue oxygen tension, together with development of novel ligands with faster distribution kinetics, faster clearance from normal tissue, and well-defined trapping mechanisms, are important goals for future investigations.344Lee, N. Y.; Mechalakos, J. G.; Nehmeh, S.; Lin, Z.; Squire, O. D.; Cai, S.; Chan, K.; Zanzonico, P. B.; Greco, C.; Ling, C. C.; Humm, J. L.; Schöder, H. Fluorine-18-Labeled Fluoromisonidazole Positron Emission and Computed Tomography-Guided Intensity-Modulated Radiotherapy for Head and Neck Cancer: A Feasibility Study. Int. Int. J. Radiat. Oncol., Biol., Phys. 2008, 70, 2– 13, DOI: 10.1016/j.ijrobp.2007.06.039[Crossref], [PubMed], [CAS], Google Scholar344https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsVentrzN&md5=6ec6605b523114de78dfe2c41cce3cccFluorine-18-Labeled Fluoromisonidazole Positron Emission and Computed Tomography-Guided Intensity-Modulated Radiotherapy for Head and Neck Cancer: A Feasibility StudyLee, Nancy Y.; Mechalakos, James G.; Nehmeh, Sadek; Lin, Zhixiong; Squire, Olivia D.; Cai, Shangde; Chan, Kelvin; Zanzonico, Pasquale B.; Greco, Carlo; Ling, Clifton C.; Humm, John L.; Schoder, HeikoInternational Journal of Radiation Oncology, Biology, Physics (2008), 70 (1), 2-13CODEN: IOBPD3; ISSN:0360-3016. (Elsevier Inc.)Purpose: Hypoxia renders tumor cells radioresistant, limiting locoregional control from radiotherapy (RT). Intensity-modulated RT (IMRT) allows for targeting of the gross tumor vol. (GTV) and can potentially deliver a greater dose to hypoxic subvolumes (GTVh) while sparing normal tissues. A Monte Carlo model has shown that boosting the GTVh increases the tumor control probability. This study examd. the feasibility of fluorine-18-labeled fluoromisonidazole positron emission tomog./computed tomog. (18F-FMISO PET/CT)-guided IMRT with the goal of maximally escalating the dose to radioresistant hypoxic zones in a cohort of head and neck cancer (HNC) patients. Methods and Materials: 18F-FMISO was administered i.v. for PET imaging. The CT simulation, fluorodeoxyglucose PET/CT, and 18F-FMISO PET/CT scans were co-registered using the same immobilization methods. The tumor boundaries were defined by clin. examn. and available imaging studies, including fluorodeoxyglucose PET/CT. Regions of elevated 18F-FMISO uptake within the fluorodeoxyglucose PET/CT GTV were targeted for an IMRT boost. Addnl. targets and/or normal structures were contoured or transferred to treatment planning to generate 18F-FMISO PET/CT-guided IMRT plans. Results: The heterogeneous distribution of 18F-FMISO within the GTV demonstrated variable levels of hypoxia within the tumor. Plans directed at performing 18F-FMISO PET/CT-guided IMRT for 10 HNC patients achieved 84 Gy to the GTVh and 70 Gy to the GTV, without exceeding the normal tissue tolerance. We also attempted to deliver 105 Gy to the GTVh for 2 patients and were successful in 1, with normal tissue sparing. Conclusion: It was feasible to dose escalate the GTVh to 84 Gy in all 10 patients and in 1 patient to 105 Gy without exceeding the normal tissue tolerance. This information has provided important data for subsequent hypoxia-guided IMRT trials with the goal of further improving locoregional control in HNC patients.345Padhani, A. R. Where Are We With Imaging Oxygenation in Human Tumours?. Cancer Imaging 2005, 5, 128– 130, DOI: 10.1102/1470-7330.2005.0103[Crossref], [PubMed], [CAS], Google Scholar345https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MnktVWrsw%253D%253D&md5=059f6113c7f0fffabb1e4f028050e481Where are we with imaging oxygenation in human tumours?Padhani Anwar RCancer imaging : the official publication of the International Cancer Imaging Society (2005), 5 (), 128-30 ISSN:.Tumour hypoxia represents a significant challenge to the curability of human tumours leading to treatment resistance and enhanced tumour regression. Tumour hypoxia can be detected by non-invasive techniques but the interrelationship between these techniques needs to be better defined. [18F]Fluoromisonidazole (18F-MISO) and Cu-labelled diacetyl-bis(N(4)-methylthiosemicarbazone (Cu-ATSM) PET, and blood oxygen level-dependent (BOLD) MRI are the lead contenders for human application based on their non-invasive nature, ease of use and robustness, measurement of hypoxia status, validity, ability to demonstrate heterogeneity and general availability; these techniques are the primary focus of this editorial.346Lapi, S. E.; Voller, T. F.; Welch, M. J. PET Imaging of Hypoxia. PET Clin 2009, 4, 39– 47, DOI: 10.1016/j.cpet.2009.05.009[Crossref], [PubMed], [CAS], Google Scholar346https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2srlvFCgtg%253D%253D&md5=74255e1aa7a6dd21fc247a3a219642a2Positron Emission Tomography Imaging of HypoxiaLapi Suzanne E; Voller Thomas F; Welch Michael JPET clinics (2009), 4 (1), 39-47 ISSN:.Hypoxia imaging has applications in functional recovery in ischemic events such as stroke and myocardial ischemia, but especially in tumors in which hypoxia can be predictive of treatment response and overall prognosis. Recently there has been development of imaging agents utilizing positron emission tomography for non-invasive imaging of hypoxia. Many of these PET agents have come to the forefront of hypoxia imaging. Halogenated PET nitroimidazole imaging agents labeled with (18)F (t(1/2) = 110 m) and (124)I (t(1/2) = 110 m) have been under investigation for the last 25 years, with radiometal agents ((64)Cu-ATSM) being developed more recently. This review focuses on these positron emission tomography imaging agents for hypoxia.347Hustinx, R.; Eck, S. L.; Alavi, A. Potential Applications of PET Imaging in Developing Novel Cancer Therapies. J. Nucl. Med. 2000, 11, 433– 441, DOI: 10.1016/S1051-0443(00)70185-0348Chen, K.; Chen, X. Positron Emission Tomography Imaging of Cancer Biology: Current Status and Future Prospects. Semin. Oncol. 2011, 38, 70– 86, DOI: 10.1053/j.seminoncol.2010.11.005[Crossref], [PubMed], [CAS], Google Scholar348https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M3jtVSlsg%253D%253D&md5=04fa5dbe375a168456211153d2ed29eePositron emission tomography imaging of cancer biology: current status and future prospectsChen Kai; Chen XiaoyuanSeminars in oncology (2011), 38 (1), 70-86 ISSN:.Positron emission tomography (PET) is one of the most rapidly growing areas of medical imaging, with many applications in the clinical management of patients with cancer. The principal goal of PET imaging is to visualize, characterize, and measure biological processes at the cellular, subcellular, and molecular levels in living subjects using noninvasive procedures. PET imaging takes advantage of the traditional diagnostic imaging techniques and introduces positron-emitting probes to determine the expression of indicative molecular targets at different stages of cancer progression. Although [(18)F]fluorodeoxyglucose ([(18)F]FDG)-PET has been widely utilized for staging and restaging of cancer, evaluation of response to treatment, differentiation of post-therapy alterations from residual or recurrent tumor, and assessment of prognosis, [(18)F]FDG is not a target-specific PET tracer. Over the last decade, numerous target-specific PET tracers have been developed and evaluated in preclinical and clinical studies. This review provides an overview of the current status and trends in the development of non-[(18)F]FDG PET probes in oncology and their application in the investigation of cancer biology.349Zhang, P.; Sadler, P. J. Redox-Active Metal Complexes for Anticancer Therapy. Eur. J. Inorg. Chem. 2017, 2017, 1541– 1548, DOI: 10.1002/ejic.201600908[Crossref], [CAS], Google Scholar349https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjsFejsrw%253D&md5=f91f0a6b258d7e3f019db364b85ab0f5Redox-Active Metal Complexes for Anticancer TherapyZhang, Pingyu; Sadler, Peter J.European Journal of Inorganic Chemistry (2017), 2017 (12), 1541-1548CODEN: EJICFO; ISSN:1434-1948. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The redox properties of both metals and ligands in transition metal complexes offer unusual routes for new mechanisms of anticancer therapy. Metal complexes can introduce artificial reductive and oxidative stress into cancer cells, including behavior as photoactivatable agents and catalysts. Relatively inert metal complexes ("prodrugs") can be activated by redox processes within cancer cells. Examples of pharmaceuticals activated by bioredn. include three PtIV and two RuIII compds. that have already entered clin. trials. More recently, novel CoIII, FeIII, PtIV, Ru(III/II), OsII, and IrIII complexes have been reported to exhibit redox-mediated anticancer activity. Redox activation strategies can introduce new methods to increase cancer cell selectivity and combat drug resistance. Using combination therapy together with redox modulators to increase potency is also possible. This essay focuses on metal complexes that are activated in the reducing environment of cancer cells.350Agdeppa, E. D.; Spilker, M. E. A Review of Imaging Agent Development. AAPS J. 2009, 11, 286– 299, DOI: 10.1208/s12248-009-9104-5[Crossref], [PubMed], [CAS], Google Scholar350https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVWqs7rK&md5=0d2de3edbeae11b64f72cc78586ec93cA review of imaging agent developmentAgdeppa, Eric D.; Spilker, Mary E.AAPS Journal (2009), 11 (2), 286-299CODEN: AJAOB6; ISSN:1550-7416. (Springer)This educational review highlights the processes, opportunities, and challenges encountered in the discovery and development of imaging agents, mainly positron emission tomog. and single-photon emission computed tomog. tracers. While the development of imaging agents parallels the drug development process, unique criteria are needed to identify opportunities for new agents. Imaging agent development has the flexibility to pursue functional or nonfunctional targets as long as they play a role in the specific disease or mechanism of interest and meet imageability requirements. However, their innovation is tempered by relatively small markets for diagnostic imaging agents, intellectual property challenges, radiolabeling constraints, and adequate target concns. for imaging. At the same time, preclin. imaging is becoming a key translational tool for proof of mechanism and concept studies. Pharmaceutical and imaging industries face a common bottleneck in the form of the limited no. of trials one company can possibly perform. However, microdosing and theranostics are evidence that partnerships between pharmaceutical and imaging companies can accelerate clin. translation of tracers and therapeutic interventions. This manuscript will comment on these aspects to provide an educational review of the discovery and development processes for imaging agents.351Miller, A.; Hoogstraten, B.; Staquet, M.; Winkler, A. Reporting Results of Cancer Treatment. Cancer 1981, 47, 207, DOI: 10.1002/1097-0142(19810101)47:1<207::AID-CNCR2820470134>3.0.CO;2-6[Crossref], [PubMed], [CAS], Google Scholar351https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL3M7htFOltw%253D%253D&md5=ced09e34265dc5a574b8cac00362492bReporting results of cancer treatmentMiller A B; Hoogstraten B; Staquet M; Winkler ACancer (1981), 47 (1), 207-14 ISSN:0008-543X.On the initiative of the World Health Organization, two meetings on the Standardization of Reporting Results of Cancer Treatment have been held with representatives and members of several organizations. Recommendations have been developed for standardized approaches to the recording of baseline data relating to the patient, the tumor, laboratory and radiologic data, the reporting of treatment, grading of acute and subacute toxicity, reporting of response, recurrence and disease-free interval, and reporting results of therapy. These recommendations, already endorsed by a number of organizations, are proposed for international acceptance and use to make it possible for investigators to compare validly their results with those of others.352O’Connell, M. PET–CT Modification of RECIST Guidelines. J. Natl. Cancer Inst. 2004, 96, 801, DOI: 10.1093/jnci/djh149[Crossref], [PubMed], [CAS], Google Scholar352https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c3ltFOhtA%253D%253D&md5=ca24eb9de8435d6ff71317085f1b5e1fPET-CT modification of RECIST guidelinesO'Connell MartinJournal of the National Cancer Institute (2004), 96 (10), 801-2; author reply 802 ISSN:.There is no expanded citation for this reference.353Frank, R. A.; Långström, B.; Antoni, G.; Montalto, M. C.; Agdeppa, E. D.; Mendizabal, M.; Wilson, I. A.; Vanderheyden, J. L. The Imaging Continuum: Bench to Biomarkers to Diagnostics. J. Labelled Compd. 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Radiotracers enable real-time in vivo studies of the effects of drug candidates on receptors, pathways, pharmacodynamics, and clin. relevant endpoints, thereby providing both early detection of pathophysiol. to enable early intervention, and then monitoring of treatment responses to enable individualization of treatment regimens. We review developments which have translated imaging from 'bench to bedside', or 'biomarkers to diagnostics'. Notable developments include (1) synthesis methods for rapid 11C labeling of biomols. to high specific radioactivity; (2) ligand-binding assays for screening mol. imaging agents rather than drugs; (3) in vivo imaging of radiotracers in animals; (4) discovering the imaging advantages of 99mTc, 11C, and 18F; (5) co-registration and automated quant. assessment of high spatial resoln. CT and MR images with mol. images from PET for longitudinal studies of treatment effect.354Robertson, C. A.; Evans, D. H.; Abrahamse, H. 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This article provides a broad review of different parameters used and mechanisms instituted in PDT such as photosensitizers (PS), photochem. and photophysics, cellular localization, cellular signaling, cell metab. and modes of cell death that operate on a cellular level, as well as photosensitizer pharmacokinetics, biodistribution, tumor localization and modes of tumor destruction. These specific cellular mechanisms are most commonly applied in PDT and for the most part are often researched and exploited. If the combination of these specific parameters and mechanisms can be optimized within PDT it could possibly be used as a suitable alternative for the treatment and management of specific cancers.355Chauhan, P.; Hadad, C.; Sartorelli, A.; Zarattini, M.; Herreros-Lopez, A.; Mba, M.; Maggini, M.; Prato, M.; Carofiglio, T. Nanocrystalline Cellulose–Porphyrin Hybrids: Synthesis, Supramolecular Properties, and Singlet-Oxygen Production. Chem. 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New Insights into the Mechanisms for Photodynamic Therapy-Induced Cancer Cell Death. Int. Rev. Cell Mol. Biol. 2012, 295, 139– 174, DOI: 10.1016/B978-0-12-394306-4.00010-1[Crossref], [PubMed], [CAS], Google Scholar358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFKgsL%252FL&md5=bdc413327941f431668a30ddfa1b4fc3New insights into the mechanisms for photodynamic therapy-induced cancer cell deathYoo, Je-Ok; Ha, Kwon-SooInternational Review of Cell and Molecular Biology (2012), 295 (), 139-174CODEN: IRCMAH; ISSN:1937-6448. (Elsevier Inc.)A review. Photodynamic therapy (PDT) is a promising therapeutic modality for cancer treatment; however, a more detailed understanding is needed to improve the clin. use of this therapy. PDT induces cancer cell death by apoptosis, necrosis, and autophagy, and these mechanisms can be concurrently occurred. PDT destroys cancer cells by inducing apoptosis through diverse signaling pathways coupled with Bcl-2 family members, caspases, and apoptosis-inducing factor. When the apoptotic pathway is unavailable, PDT can cause cancer cell death through induction of a necrotic or autophagic mechanism. Autophagy is occurred in a Bax-independent manner and can be stimulated in parallel with apoptosis. PDT directly destroys cancer cells by inducing either apoptotic or necrotic death. PDT also can induce autophagy as a death or a survival mechanism. These mechanisms are dependent on a variety of parameters including the nature of the photosensitizer, PDT dose, and cell genotype. Understanding the complex cross talk between these pathways may improve the effectiveness of PDT. Here, we discuss the interplay between these mechanisms based on recent evidence and suggest prospects with regard to advances in PDT.359Li, S. Y.; Xie, B. R.; Cheng, H.; Li, C. X.; Zhang, M. K.; Qiu, W. X.; Liu, W. L.; Wang, X. S.; Zhang, X. Z. A Biomimetic Theranostic O2-Meter for Cancer Targeted Photodynamic Therapy and Phosphorescence Imaging. Biomaterials 2018, 151, 1– 12, DOI: 10.1016/j.biomaterials.2017.10.021[Crossref], [PubMed], [CAS], Google Scholar359https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1GktLjM&md5=c3133ddb302d6e7ee32bfc62bc372db4A biomimetic theranostic O2-meter for cancer targeted photodynamic therapy and phosphorescence imagingLi, Shi-Ying; Xie, Bo-Ru; Cheng, Hong; Li, Chu-Xin; Zhang, Ming-Kang; Qiu, Wen-Xiu; Liu, Wen-Long; Wang, Xiao-Shuang; Zhang, Xian-ZhengBiomaterials (2018), 151 (), 1-12CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)In this report, a biomimetic theranostic oxygen (O2)-meter (cancer cell [email protected](II) porphyrinic-metal org. framework, designated as mPPt) was constructed for cancer targeted and phosphorescence image-guided photodynamic therapy (PDT). mPPt presents high photosensitizers (PSs) loading and evitable self-quenching behaviors for favorable biol. O2 sensing and PDT. Besides, endowed by the surface functionalization of cancer cell membrane, the homotypic targeting and immune escape abilities of mPPt could dramatically enhance its cancer targeting ability. Importantly, the O2-dependent phosphorescence responsibility of mPPt could be employed to pre-evaluate the real time O2 level in situ and guide the PDT under light irradn. A significant anticancer effect is obsd. after i.v. injection of mPPt and subsequent treatment with PDT with no obvious side effects. As a versatile platform for cell imaging, O2 fluctuation monitoring as well as PDT, this biomimetic O2-meter exhibits great potential for biol. anal. and personalized cancer theranostics.
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Abstract
Figure 1
Figure 1. Imaging applications in photodynamic therapy.
Figure 2
Figure 2. Cartoon depicting personalized medicine with theranostic agents.
Figure 3
Figure 3. Ideal characteristics of photosensitizers.
Figure 4
Figure 4. Structures of photosensitizers currently used in PDT.
Figure 5
Figure 5. Most commonly used PSs in the clinic.
Figure 6
Figure 6. Two main strategies to accomplish tumor-targeted PDT.
Figure 7
Figure 7. Receptor-targeted approach in PDT.
Figure 8
Figure 8. Structures of conjugated PSs.
Figure 9
Figure 9. Illustration of a theranostic agent for PDT with a D–A–D structure with enhanced 1O2, QYs, and fluorescence.
Figure 10
Figure 10. Principles behind a beacon system for post-PDT imaging of apoptosis.(184) The system is composed of four parts: a PS (violet dot), a folate delivery entity (blue dot), a caspase-3 cleavable linker (KGDEVDGSGK), and a quencher (red dot).
Figure 11
Figure 11. Pyro-GDEVDGSGK-Folate comprising three components: pyropheophorbide-a (imaging and therapeutic agent), a peptide sequence (linker), and folate (delivery vehicle).
Scheme 1
Scheme 1. Synthesis of [64Cu]CuPPIX (Protoporphyrin IX)(141)Figure 12
Figure 12. Multifunctional nanoplatform for cancer imaging and therapy with radiolabeled (124I) chlorophyll-a (right) and the nonradioactive analogue (left), showing the accumulation in the tumor.(3)
Scheme 2
Scheme 2. Synthesis of 64Cu-Labeled Phthalocyanines(200)Figure 13
Figure 13. In vivo multimodal imaging of [64Cu]-Cu(II)-porphysomes in an orthotropic prostate cancer model.(192)
Figure 14
Figure 14. Structures of Cyanine-Based NIR dyes.
Scheme 3
Scheme 3. Mechanism of Nitroimidazole Derivatives in Hypoxic CellsFigure 15
Figure 15. Proposed mechanism of hypoxic selectivity for [64Cu]CuATSM.(247,251,252)
Figure 16
Figure 16. Studies showing the relationships between the retention of [18F]FMISO and [64Cu]Cu(ATSM) and hypoxia. (a) Coregistration of the [18F]FMISO PET signal (2 h postinjection) with the [64Cu]Cu(ATSM) PET signal (3 or 24 h postinjection. (b) [18F]FMISO and [64Cu]Cu(ATSM) uptake was evaluated at 2 and 24 h after radiotracer injection, respectively.(260)
Figure 17
Figure 17. Schematic PAA core matrix nanoplatform with photodynamic dye, MRI contrast agent, polyethylene glycol (PEG) loading, and molecular targeting groups.(172)
Figure 18
Figure 18. Iodobenzylpyropheophorbide precursor for functionalization to ORMOSIL NPs.
Figure 19
Figure 19. Cartoon illustrating the surface plasmon resonance phenomena on gold NPs.
Figure 20
Figure 20. Mechanism of an activatable peptidic zipper-based PS.
Figure 21
Figure 21. Structures of known [18F]-based 2-nitroimidazole derivatives.
Scheme 4
Scheme 4. Synthesis of Cellulose-Metallo-Porphyrin Theranostic AgentsReferences
ARTICLE SECTIONSThis article references 359 other publications.
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- 4Evans, C. L.; Rizvi, I.; Hasan, T.; Boer, J. F. de. Vitro Ovarian Tumor Growth and Treatment Response Dynamics Visualized With Time-Lapse OCT Imaging. Opt. Express 2009, 17, 8892, DOI: 10.1364/OE.17.008892[Crossref], [PubMed], [CAS], Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXms1Cqsro%253D&md5=930f5d83d451a5110c391d524b943777In vitro ovarian tumor growth and treatment response dynamics visualized with time-lapse OCT imagingEvans, Conor L.; Rizvi, Imran; Hasan, Tayyaba; de Boer, Johannes F.Optics Express (2009), 17 (11), 8892-8906CODEN: OPEXFF; ISSN:1094-4087. (Optical Society of America)In vitro three-dimensional models for metastatic ovarian cancer have been useful for recapitulating the human disease. These spheroidal tumor cultures, however, can grow in excess of 1 mm in diam., which are difficult to visualize without suitable imaging technol. Optical coherence tomog. (OCT) is an ideal live imaging method for non-perturbatively visualizing these complex systems. OCT enabled detailed observations of the model at both nodular and cellular levels, revealing growth dynamics not previously obsd. The development of a time-lapse OCT system, capable of automated, multidimensional acquisition, further provided insights into the growth and chemotherapeutic response of ovarian cancer.
- 5Georgakoudi, I.; Solban, N.; Novak, J.; Rice, W. L.; Wei, X.; Hasan, T.; Lin, C. P. In Vivo Flow Cytometry: A New Method for Enumerating Circulating Cancer Cells. Cancer Res. 2004, 64, 5044– 5047, DOI: 10.1158/0008-5472.CAN-04-1058[Crossref], [PubMed], [CAS], Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmtF2mtrg%253D&md5=287c482b11553445b03f47ce8275601bIn Vivo Flow Cytometry: A New Method for Enumerating Circulating Cancer CellsGeorgakoudi, Irene; Solban, Nicolas; Novak, John; Rice, William L.; Wei, Xunbin; Hasan, Tayyaba; Lin, Charles P.Cancer Research (2004), 64 (15), 5044-5047CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)The fate of circulating tumor cells is an important determinant of their ability to form distant metastasis. Here, we demonstrate the use of in vivo flow cytometry as a powerful new method for detecting quant. circulating cancer cells. We specifically examine the circulation kinetics of two prostate cancer cell lines with different metastatic potential in mice and rats. We find that the cell line and the host environment affect the circulation kinetics of prostate cancer cells, with the intrinsic cell line properties detg. the initial rate of cell depletion from the circulation and the host affecting cell circulation at later time points.
- 6Solban, N.; Pal, S. K.; Alok, S. K.; Sung, C. K.; Hasan, T. Mechanistic Investigation and Implications of Photodynamic Therapy Induction of Vascular Endothelial Growth Factor in Prostate Cancer. Cancer Res. 2006, 66, 5633– 5640, DOI: 10.1158/0008-5472.CAN-06-0604[Crossref], [PubMed], [CAS], Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XltFyjt7o%253D&md5=3086bf398ec261c44d8359d261c46b35Mechanistic Investigation and Implications of Photodynamic Therapy Induction of Vascular Endothelial Growth Factor in Prostate CancerSolban, Nicolas; Pal, Selbo K.; Alok, Sinha K.; Sung, Chang K.; Hasan, TayyabaCancer Research (2006), 66 (11), 5633-5640CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Photodynamic therapy (PDT) is now an approved therapeutic modality, and induction of vascular endothelial growth factor (VEGF) following subcurative PDT is of concern as VEGF may provide a survival stimulus to tumors. The processes that limit the efficacy of PDT warrant investigation so that mechanism-based interventions may be developed. This study investigates VEGF increase following subcurative PDT using the photosensitizer benzoporphyrin deriv. (BPD) both in an in vitro and in an orthotopic model of prostate cancer using the human prostate cancer cell line LNCaP. The two subcurative doses used, 0.25 and 0.5 J/cm2, mimicked subcurative PDT and elicited a 1.6- and 2.1-fold increase, resp., in secreted VEGF 24 h following PDT. Intracellular VEGF protein measurement and VEGF mRNA showed a 1.4- and 1.6-fold increase only at 0.5 J/cm2. In vivo subcurative PDT showed an increase in VEGF by both immunohistochem. and ELISA. In vitro anal. showed no activation of hypoxia-inducible factor-1α (HIF-1α) or cyclooxygenase-2 (COX-2) following subcurative PDT; furthermore, small interfering RNA inhibition of HIF-1α and COX-2 inhibitor treatment had no effect on PDT induction of VEGF. PDT in the presence of phosphatidylinositol 3-kinase/AKT inhibitor or mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase inhibitor still induced VEGF. However, subcurative PDT increased phosphorylated p38 and stress-activated protein kinase/c-Jun NH2-terminal kinase. The p38 MAPK inhibitor abolished PDT induction of VEGF. The results establish the importance of VEGF in subcurative BPD-PDT of prostate cancer and suggest possible mol. pathways for its induction. These findings should provide the basis for the development of mol.-based interventions for enhancing PDT and merit further studies.
- 7Abrahamse, H.; Hamblin, M. R. New Photosensitizers for Photodynamic Therapy. Biochem. J. 2016, 473, 347– 364, DOI: 10.1042/BJ20150942[Crossref], [PubMed], [CAS], Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xitleqsrc%253D&md5=9ad9b594476ad2c3452189212f0827b7New photosensitizers for photodynamic therapyAbrahamse, Heidi; Hamblin, Michael R.Biochemical Journal (2016), 473 (4), 347-364CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)Photodynamic therapy (PDT) was discovered more than 100 years ago, and has since become a well-studied therapy for cancer and various non-malignant diseases including infections. PDT uses photosensitizers (PSs, non-toxic dyes) that are activated by absorption of visible light to initially form the excited singlet state, followed by transition to the long-lived excited triplet state. This triplet state can undergo photochem. reactions in the presence of oxygen to form reactive oxygen species (including singlet oxygen) that can destroy cancer cells, pathogenic microbes and unwanted tissue. The dual-specificity of PDT relies on accumulation of the PS in diseased tissue and also on localized light delivery. Tetrapyrrole structures such as porphyrins, chlorins, bacteriochlorins and phthalocyanines with appropriate functionalization have been widely investigated in PDT, and several compds. have received clin. approval. Other mol. structures including the synthetic dyes classes as phenothiazinium, squaraine and BODIPY (boron-dipyrromethene), transition metal complexes, and natural products such as hypericin, riboflavin and curcumin have been investigated. Targeted PDT uses PSs conjugated to antibodies, peptides, proteins and other ligands with specific cellular receptors. Nanotechnol. has made a significant contribution to PDT, giving rise to approaches such as nanoparticle delivery, fullerene-based PSs, titania photocatalysis, and the use of upconverting nanoparticles to increase light penetration into tissue. Future directions include photochem. internalization, genetically encoded protein PSs, theranostics, two-photon absorption PDT, and sonodynamic therapy using ultrasound.
- 8Gibbs-Strauss, S. L. Noninvasive Measurement of Aminolevulinic Acid-Induced Protoporphyrin IX Fluorescence Allowing Detection of Murine Glioma in Vivo. J. Biomed. Opt. 2009, 14, 014007, DOI: 10.1117/1.3065543[Crossref], [PubMed], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXisFeksb8%253D&md5=1d3d09a8eff3d562bd2993909433a466Noninvasive measurement of aminolevulinic acid-induced protoporphyrin IX fluorescence allowing detection of murine glioma in vivoGibbs-Strauss, Summer L.; O'Hara, Julia A.; Hoopes, P. Jack; Hasan, Tayyaba; Pogue, Brian W.Journal of Biomedical Optics (2009), 14 (1), 014007/1-014007/8CODEN: JBOPFO; ISSN:1083-3668. (Society of Photo-Optical Instrumentation Engineers)Aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence is studied as a contrast agent for noninvasive detection of murine glioma, using the fluorescence-to-transmission ratio measured through the cranium. Signals measured prior to administration of ALA are very similar between control animals, 9L-GFP, and U251 tumor-bearing animals. However, 2 h after ALA administration, the PpIX signal from both tumor-bearing groups is significantly higher than the control group (9L-GFP group p-value=0.016, and U251 group p-value=0.004, relative to the control group). The variance in signal from the 9L-GFP group is much larger than either the control group or the U251 group, which is consistent with higher intrinsic PpIX fluorescence heterogeneity as seen in situ at ex vivo anal. Decreasing the skin PpIX fluorescence via intentional photobleaching using red light (635 nm) is examd. as a tool for increasing PpIX contrast between the tumor-bearing and control groups. The red light bleaching is found to increase the ability to accurately quantify PpIX fluorescence in vivo, but decreases the specificity of detection between tumor-bearing and nontumor-bearing groups.
- 9Soukos, N. S.; Hamblin, M. R.; Keel, S.; Fabian, R. L.; Deutsch, T. F.; Hasan, T. Epidermal Growth Factor Receptor-Targeted Immunophotodiagnosis and Photoimmunotherapy of Oral Precancer in Vivo. Cancer Res. 2001, 61, 4490– 4496[PubMed], [CAS], Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXktlWjs70%253D&md5=c13385de1e227db9fa7cb18bc002cacbEpidermal growth factor receptor-targeted immunophotodiagnosis and photoimmunotherapy of oral precancer in vivoSoukos, Nikolaos S.; Hamblin, Michael R.; Keel, Suzanne; Fabian, Richard L.; Deutsch, Thomas F.; Hasan, TayyabaCancer Research (2001), 61 (11), 4490-4496CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Immunophotodiagnosis uses a fluorescence-labeled monoclonal antibody (MAb) that recognizes a tumor-assocd. antigen to image the fluorescence emitted from the fluorophore-bound MAb that has localized in the tissue. It may be used to diagnose malignant or precancerous lesions, to delineate the margins for tumor resection, or as a feedback mechanism to assess response to treatment. In oral precancer, the epidermal growth factor receptor (EGFR) is overexpressed and could be used as a marker for early detection or as a target for therapy. The goal of this study was to test an anti-EGFR MAb (C225) coupled to either the near-IR fluorescent dye N,N'-di-carboxypentyl-indodicarbocyanine-5,5'-disulfonic acid for detection or a photochem. active dye (chlorine6) for therapy of early premalignancy in the hamster cheek pouch carcinogenesis model. Fluorescence levels in the carcinogen-treated tissue correlated with the histol. stage of the lesions when the C225-N,N'-di-carboxypentyl-indodicarbocyanine-5,5'-disulfonic acid conjugate was used but did not do so with the irrelevant conjugates. Discrete areas of clin. normal mucosa with high fluorescence (hot spots) were subsequently shown by histol. to contain dysplastic areas. The best contrast between normal and carcinogen-treated cheek pouches was found at 4-8 days after injection. To test the potential of immunophotodiagnosis as a feedback modality for therapeutic intervention, expts. were conducted with the same MAb conjugated to chlorine6 followed by illumination to reduce expression of the EGFR by a photodynamic effect. Subsequent immunophotodiagnosis showed that this treatment led to a significant redn. in fluorescence in the carcinogen-treated cheek pouch compared with nonilluminated areas. This difference between illuminated and dark areas was not seen in the normal cheek pouch. Taken together, the results demonstrate the potential for development of immunophotodiagnosis as a diagnostic tool and as a method of monitoring response to therapy and that the EGFR may be an appropriate target in head and neck cancer.
- 10Zheng, X.; Sallum, U. W.; Verma, S.; Athar, H.; Evans, C. L.; Hasan, T. Exploiting a Bacterial Drug-Resistance Mechanism: A Light-Activated Construct for the Destruction of MRSA. Angew. Chem., Int. Ed. 2009, 48, 2148– 2151, DOI: 10.1002/anie.200804804[Crossref], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXktFegtr4%253D&md5=aa3ee1067024a7174bae31b1b240fcdeExploiting a bacterial drug-resistance mechanism: a light-activated construct for the destruction of MRSAZheng, Xiang; Sallum, Ulysses W.; Verma, Sarika; Athar, Humra; Evans, Conor L.; Hasan, TayyabaAngewandte Chemie, International Edition (2009), 48 (12), 2148-2151CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)An enzyme-specific mol. construct exploits the overexpression of β-lactamase in several drug-resistant bacteria. Ed Specific photodynamic toxicity was detected towards β-lactam-resistant methicillin-resistant Staphylococcus aureus (MRSA), whereby the usual mechanism for antibiotic resistance (cleavage of the β-lactam ring) releases the phototoxic component from the prodrug.
- 11Zhong, W.; Celli, J. P.; Rizvi, I.; Mai, Z.; Spring, B. Q.; Yun, S. H.; Hasan, T. In Vivo High-Resolution Fluorescence Microendoscopy for Ovarian Cancer Detection and Treatment Monitoring. Br. J. Cancer 2009, 101, 2015– 2022, DOI: 10.1038/sj.bjc.6605436[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFaqtr7M&md5=4b2a5cf6e044243d4bc51f309d0565f0In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoringZhong, W.; Celli, J. P.; Rizvi, I.; Mai, Z.; Spring, B. Q.; Yun, S. H.; Hasan, T.British Journal of Cancer (2009), 101 (12), 2015-2022CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)Background: In patients with advanced ovarian cancer (OvCa), microscopic residual tumor nodules that remain after surgical debulking frequently escape detection by current treatment assessment methods and lead to disease recurrence. The aim of this study was to evaluate the use of high-resoln. fiber-optic fluorescence imaging of the clin. approved photodynamic therapy (PDT) agent benzoporphyin-deriv. monoacid ring A (BPD-MA) for detection of microscopic OvCa and for monitoring treatment response. Methods: Our fluorescence microendoscope consists of a flexible imaging fiber coupled to a custom epi-fluorescence system optimized for imaging BPD-MA, which, after a single administration, serves as both an imaging agent and a light-activated therapeutic agent. After characterization in an in vitro OvCa 3D model, we used the flexible imaging fiber to minimally invasively image the peritoneal cavity of a disseminated OvCa murine model using BPD-MA administered i.p. To evaluate longitudinal changes in response to treatment, we compared sets of images obtained before and after PDT with those from untreated mice imaged at the same time points. Results: By comparison with histopathol., we report an 86% sensitivity for tumor detection in vivo using the microendoscope. Using a custom routine to batch process-image data in the monitoring study, treated mice exhibited an av. decrease of 58.8% in tumor vols. compared with an increase of 59.3% in untreated controls (P<0.05). Conclusions: Our findings indicate the potential of this approach as a reporter of treatment outcome that could aid in the rational design of strategies to mitigate recurrent OvCa.
- 12Li, Y.; Wang, J.; Zhang, X.; Guo, W.; Li, F.; Yu, M.; Kong, X.; Wu, W.; Hong, Z. Highly Water-Soluble and Tumor-Targeted Photosensitizers for Photodynamic Therapy. Org. Biomol. Chem. 2015, 13, 7681– 7694, DOI: 10.1039/C5OB01035G[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpsF2ns7k%253D&md5=321d533f0a3356ccdde82d4735e8a1f2Highly water-soluble and tumor-targeted photosensitizers for photodynamic therapyLi, Yuxi; Wang, Jin; Zhang, Xiaoxiao; Guo, Wenjun; Li, Fu; Yu, Min; Kong, Xiuqi; Wu, Wenjie; Hong, ZhangyongOrganic & Biomolecular Chemistry (2015), 13 (28), 7681-7694CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)Biol. uses of photosensitizers in photodynamic therapy (PDT) often suffer from a lack of tumor selectivity; a strategy based on mol.-targeted cancer therapies could provide a promising soln. To synthesize new water-sol. phthalocyanines (Pcs) for bio-conjugation with peptides or antibodies, we developed a method to synthesize asym. substituted Pcs with both high water soly. and one monoamino group for conjugation with biol. agents for tumor homing, using folic acid as the ligand model to direct the modified Pcs into target cells. Here, we report studies on the syntheses and characterization of these Pcs. In vitro and in vivo assays prove that the high soly. characteristic can greatly increase the tumor targeting capability of Pcs by reducing non-specific uptake. This newly designed photosensitizer accumulated almost completely in tumor regions, with a negligible signal found in other tissues in the xenograft tumor model. These initial data provide strong evidence of the high specificity tumor targeting of Pcs with folate and tri-glycerol substitutions. Theor., the synthesized Pcs could be conveniently conjugated to many other ligands, endorsing the broad applicability of this method for tumor-targeted PDT.
- 13Celli, J. P.; Spring, B. Q.; Rizvi, I.; Evans, C. L.; Samkoe, K. S.; Verma, S.; Pogue, B. W.; Hasan, T. Imaging and Photodynamic Therapy: Mechanisms, Monitoring, and Optimization. Chem. Rev. 2010, 110, 2795– 2838, DOI: 10.1021/cr900300p[ACS Full Text], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXktVeqt7o%253D&md5=43f42186964bfb1227739a8acaf82077Imaging and Photodynamic Therapy: Mechanisms, Monitoring, and OptimizationCelli, Jonathan P.; Spring, Bryan Q.; Rizvi, Imran; Evans, Conor L.; Samkoe, Kimberley S.; Verma, Sarika; Pogue, Brian W.; Hasan, TayyabaChemical Reviews (Washington, DC, United States) (2010), 110 (5), 2795-2838CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review.
- 14Kharroubi Lakouas, D.; Huglo, D.; Mordon, S.; Vermandel, M. Nuclear Medicine for Photodynamic Therapy in Cancer: Planning, Monitoring and Nuclear PDT. Photodiagn. Photodyn. Ther. 2017, 18, 236– 243, DOI: 10.1016/j.pdpdt.2017.03.002[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmtlahsbk%253D&md5=de9343b97724f6c80c8fb527088ba36aNuclear medicine for photodynamic therapy in cancer: Planning, monitoring and nuclear PDTKharroubi Lakouas, Dris; Huglo, Damien; Mordon, Serge; Vermandel, MaximilienPhotodiagnosis and Photodynamic Therapy (2017), 18 (), 236-243CODEN: PPTHBF; ISSN:1572-1000. (Elsevier B.V.)A review. Photodynamic therapy (PDT) is a modality with promising results for the treatment of various cancers. PDT is increasingly included in the std. of care for different pathologies. This therapy relies on the effects of light delivered to photosensitized cells. At different stages of delivery, PDT requires imaging to plan, evaluate and monitor treatment. The contribution of mol. imaging in this context is important and continues to increase. In this article, we review the contribution of nuclear medicine imaging in oncol. to PDT for planning and therapeutic monitoring purposes. Several solns. have been proposed to plan PDT from nuclear medicine imaging. For instance, photosensitizer biodistribution has been evaluated with a radiolabeled photosensitizer or with conventional radiopharmaceuticals on positron emission tomog. The effects of PDT delivery have also been explored with specific SPECT or PET radiopharmaceuticals to evaluate the effects on cells (apoptosis, necrosis, proliferation, metab.) or vascular damage. Finally, the synergy between photosensitizers and radiopharmaceuticals has been studied considering the Cerenkov effect to activate photosensitized cells.
- 15Jokerst, J. V.; Lobovkina, T.; Zare, R. N.; Gambhir, S. S. Nanoparticle PEGylation for Imaging and Therapy. Nanomedicine 2011, 6, 715– 728, DOI: 10.2217/nnm.11.19[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsVajtro%253D&md5=960e4aed2f95aae187beeb7d6e5eb882Nanoparticle PEGylation for imaging and therapyJokerst, Jesse V.; Lobovkina, Tatsiana; Zare, Richard N.; Gambhir, Sanjiv S.Nanomedicine (London, United Kingdom) (2011), 6 (4), 715-728CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)A review. Nanoparticles are an essential component in the emerging field of nanomedical imaging and therapy. When deployed in vivo, these materials are typically protected from the immune system by polyethylene glycol (PEG). A wide variety of strategies to coat and characterize nanoparticles with PEG has established important trends on PEG size, shape, d., loading level, mol. wt., charge and purifn. Strategies to incorporate targeting ligands are also prevalent. This article presents a background to investigators new to stealth nanoparticles, and suggests some key considerations needed prior to designing a nanoparticle PEGylation protocol and characterizing the performance features of the product.
- 16Crawley, N.; Thompson, M.; Romaschin, A. Theranostics in the Growing Field of Personalized Medicine: An Analytical Chemistry Perspective. Anal. Chem. 2014, 86, 130– 160, DOI: 10.1021/ac4038812[ACS Full Text], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFSqsb3J&md5=96501281b0737b9f17c2500c784489a7Theranostics in the Growing Field of Personalized Medicine: An Analytical Chemistry PerspectiveCrawley, Niall; Thompson, Michael; Romaschin, AlexanderAnalytical Chemistry (Washington, DC, United States) (2014), 86 (1), 130-160CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)A review. The purpose of this article is more than a review of theranostics and nanoparticles. It is our intention to also pose questions and discuss the challenges of the future of this field. We attempt to show how, in our opinion; the anal. chemist can feature prominently in the upcoming successes of this field. This is a "hot" area of research and there is much that the anal. chemist can contribute moving forward. We will also introduce a new sub-field based on the first definition of theranostics above. Instrumental or macro-theranostics describes the development of macro-scale instruments capable of both diagnostics and therapy. In particular we introduce theranostic circuit devices (TCDs) that consist of extracorporeal circulation of the blood and the use of an inline imaging system with a therapeutic cartridge component to clean and remove harmful mols. or cells from the bloodstream.
- 17Kelkar, S. S.; Reineke, T. M. Theranostics: Combining Imaging and Therapy. Bioconjugate Chem. 2011, 22, 1879– 1903, DOI: 10.1021/bc200151q[ACS Full Text], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtV2jt77K&md5=54add18153e2ad4c9c2aa30ba97dbc6dTheranostics: Combining Imaging and TherapyKelkar, Sneha S.; Reineke, Theresa M.Bioconjugate Chemistry (2011), 22 (10), 1879-1903CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)A review. Employing theranostic nanoparticles, which combine both therapeutic and diagnostic capabilities in one dose, has promise to propel the biomedical field toward personalized medicine. This review presents an overview of different theranostic strategies developed for the diagnosis and treatment of disease, with an emphasis on cancer. Herein, therapeutic strategies such as nucleic acid delivery, chemotherapy, hyperthermia (photothermal ablation), photodynamic, and radiation therapy are combined with one or more imaging functionalities for both in vitro and in vivo studies. Different imaging probes, such as MRI contrast agents (T1 and T2 agents), fluorescent markers (org. dyes and inorg. quantum dots), and nuclear imaging agents (PET/SPECT agents), can be decorated onto therapeutic agents or therapeutic delivery vehicles in order to facilitate their imaging and, in so doing, gain information about the trafficking pathway, kinetics of delivery, and therapeutic efficacy; several such strategies are outlined. The creative approaches being developed for these classes of therapies and imaging modalities are discussed, and the recent developments in this field along with examples of technologies that hold promise for the future of cancer medicine are highlighted.
- 18Terreno, E.; Uggeri, F.; Aime, S. Image Guided Therapy: The Advent of Theranostic Agents. J. Controlled Release 2012, 161, 328– 337, DOI: 10.1016/j.jconrel.2012.05.028[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xot12jurs%253D&md5=47cafb00bcfdfee02ac05cc610f1f389Image guided therapy: The advent of theranostic agentsTerreno, Enzo; Uggeri, Fulvio; Aime, SilvioJournal of Controlled Release (2012), 161 (2), 328-337CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Theranostic agents represent a recently introduced class of imaging probes designed to offer to pharmacologists and physicians a robust tool for minimally invasive in vivo visualization of drug delivery/release and therapy monitoring. By means of these agents, novel strategies able to integrate diagnosis and therapy could be developed. This highly interdisciplinary research field is one of the more innovative products resulting from the synergism between mol. imaging and nanomedicine. Potential applications of theranosis include the in vivo assessment of drug biodistribution and accumulation at the target site, visualization of the drug release from a given nanocarrier, and real-time monitoring of the therapeutic outcome. The expected end-point of theranostic agents is to provide a fundamental support for the optimization of innovative diagnostic and therapeutic strategies that could contribute to emerging concepts in the field of the "personalized medicine". This perspective paper aims at providing the reader the basic principles of theranosis with a particular emphasis to the design of theranostic agents.
- 19Yoon, H. Y.; Jeon, S.; You, D. G.; Park, J. H.; Kwon, I. C.; Koo, H.; Kim, K. Inorganic Nanoparticles for Image-Guided Therapy. Bioconjugate Chem. 2017, 28, 124– 134, DOI: 10.1021/acs.bioconjchem.6b00512[ACS Full Text], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslGku7%252FM&md5=352e2f7f97fd9f4f56c7c5c6f58ad9efInorganic Nanoparticles for Image-Guided TherapyYoon, Hong Yeol; Jeon, Sangmin; You, Dong Gil; Park, Jae Hyung; Kwon, Ick Chan; Koo, Heebeom; Kim, KwangmeyungBioconjugate Chemistry (2017), 28 (1), 124-134CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)A review. Recently, nanotechnol. has provided significant advances in biomedical applications including diagnosis and therapy. In particular, nanoparticles have emerged as valuable outcomes of nanotechnol. due to their unique physicochem. properties based on size, shape, and surface properties. Among them, a large amt. of research has reported imaging and therapeutic applications using inorg. nanoparticles with special properties. Inorg. nanoparticles developed for imaging and therapy contain metal (Au), metal oxide (Fe3O4, WO3, WO2.9), semiconductor nanocrystal (quantum dots (QDs)), and lanthanide-doped upconversion nanoparticles (UCNPs). Based on their intrinsic properties, they can generate heat, reactive oxygen species (ROS), or energy transfer, so that they can be used for both imaging and therapy. In this review, the authors introduce biocompatible inorg. nanoparticles for image-guided thermal and photodynamic therapy, and discuss their promising results from in vitro and in vivo studies for biomedical applications.
- 20Jenni, S.; Sour, A. Molecular Theranostic Agents for Photodynamic Therapy (PDT) and Magnetic Resonance Imaging (MRI). Inorganics 2019, 7, 10, DOI: 10.3390/inorganics7010010[Crossref], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht1SjsL3O&md5=46778d963f5504fa0e6b4abc79b39feeMolecular theranostic agents for photodynamic therapy (PDT) and magnetic resonance imaging (MRI)Jenni, Sebastien; Sour, AngeliqueInorganics (2019), 7 (1), 10CODEN: INORCW; ISSN:2304-6740. (MDPI AG)Magnetic resonance imaging (MRI) is a powerful non-invasive diagnostic tool that can provide important insights for medical treatment monitoring and optimization. Photodynamic therapy (PDT), a minimally invasive treatment for various types of tumors, is drawing increasing interest thanks to its temporal and spatial selectivity. The combination of MRI and PDT offers real-time monitoring of treatment and can give significant information for drug-uptake and light-delivery parameters optimization. In this review we will give an overview of mol. theranostic agents that have been designed for their potential application in MRI and PDT.
- 21Dougherty, T. J. Hematoporphyrin Derivative for Detection and Treatment of Cancer. J. Surg. Oncol. 1980, 15, 209– 210, DOI: 10.1002/jso.2930150303[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL3M%252FltVOnug%253D%253D&md5=c6e613e85c5e06578f3268169e0c37dcHematoporphyrin derivative for detection and treatment of cancerDougherty T JJournal of surgical oncology (1980), 15 (3), 209-10 ISSN:0022-4790.There is no expanded citation for this reference.
- 22Allison, R. R. Photodynamic Therapy: Oncologic Horizons. Future Oncol. 2014, 10, 123– 142, DOI: 10.2217/fon.13.176[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvV2rsbbI&md5=b676b2bb7b36db28ec9e5ae99520e1dePhotodynamic therapy: oncologic horizonsAllison, Ron R.Future Oncology (2014), 10 (1), 123-124CODEN: FOUNBN; ISSN:1479-6694. (Future Medicine Ltd.)A review. Photodynamic therapy (PDT) is a light-based intervention with a long and successful clin. track record for both oncol. and non-malignancies. In cancer patients, a photosensitizing agent is i.v., orally or topically applied and allowed time to preferentially accumulate in the tumor region. Light of the appropriate wavelength and intensity to activate the particular photosensitizer employed is then introduced to the tumor bed. The light energy will activate the photosensitizer, which in the presence of oxygen should allow for creation of the toxic photodynamic reaction generating reactive oxygen species. The photodynamic reaction creates a cascading series of events including initiation of apoptotic and necrotic pathways both in tumor and neovasculature, leading to permanent lesion destruction often with upregulation of the immune system. Cutaneous phototoxicity from unintentional sunlight exposure remains the most common morbidity from PDT. This paper will highlight current research and outcomes from the basic science and clin. applications of oncol. PDT and interpret how these findings may lead to enhanced and refined future PDT.
- 23Calin, M. A.; Parasca, S. V. Photodynamic Therapy in Oncology. J. Optoelectron. Adv. Mater. 2006, 8, 1173– 1179
- 24Verma, S.; Watt, G. M.; Mai, Z.; Hasan, T. Strategies for Enhanced Photodynamic Therapy Effects. Photochem. Photobiol. 2007, 83, 996– 1005, DOI: 10.1111/j.1751-1097.2007.00166.x[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFGhurvE&md5=47011ef7222ca16fb6b7c829bfec16d4Strategies for enhanced photodynamic therapy effectsVerma, Sarika; Watt, Gregory M.; Mai, Zhiming; Hasan, TayyabaPhotochemistry and Photobiology (2007), 83 (5), 996-1005CODEN: PHCBAP; ISSN:0031-8655. (Blackwell Publishing, Inc.)A review. Photodynamic therapy (PDT) is a treatment modality for the selective destruction of cancerous and nonneoplastic pathologies that involves the simultaneous presence of light, oxygen and a light-activatable chem. called a photosensitizer (PS) to achieve a cytotoxic effect. The photophysics and mechanisms of cell killing by PDT have been extensively studied in recent years, and PDT has received regulatory approval for the treatment of a no. of diseases worldwide. As the application of this treatment modality expands with regard to both anatomical sites and disease stages, it will be important to develop strategies for enhancing PDT outcomes. This article focuses on two broad approaches for PDT enhancement:. (1) Mechanism-based combination treatments in which PDT and a second modality can be designed to either increase the susceptibility of tumor cells to PDT or nullify the treatment outcome-mitigating mol. responses triggered by PDT of tumors, and. (2) The more recent approaches of PS targeting, either by specific cellular function-sensitive linkages or via conjugation to macromols.
- 25Spring, B. Q.; Abu-Yousif, A. O.; Palanisami, A.; Rizvi, I.; Zheng, X.; Mai, Z.; Anbil, S.; Sears, R. B.; Mensah, L. B.; Goldschmidt, R.; Erdem, S. S.; Oliva, E.; Hasan, T. Selective Treatment and Monitoring of Disseminated Cancer Micrometastases in Vivo Using Dual-Function, Activatable Immunoconjugates. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, E933– E942, DOI: 10.1073/pnas.1319493111[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtlyltL0%253D&md5=f38a0ccfb5e65237477f2409c4d63bcdSelective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugatesSpring, Bryan Q.; Abu-Yousif, Adnan O.; Palanisami, Akilan; Rizvi, Imran; Zheng, Xiang; Mai, Zhiming; Anbil, Sriram; Sears, R. Bryan; Mensah, Lawrence B.; Goldschmidt, Ruth; Erdem, S. Sibel; Oliva, Esther; Hasan, TayyabaProceedings of the National Academy of Sciences of the United States of America (2014), 111 (10), E933-E942CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Drug-resistant micrometastases that escape std. therapies often go undetected until the emergence of lethal recurrent disease. Here, we show that it is possible to treat microscopic tumors selectively using an activatable immunoconjugate. The immunoconjugate is composed of self-quenching, near-IR chromophores loaded onto a cancer cell-targeting antibody. Chromophore phototoxicity and fluorescence are activated by lysosomal proteolysis, and light, after cancer cell internalization, enabling tumor-confined photocytotoxicity and resoln. of individual micrometastases. This unique approach not only introduces a therapeutic strategy to help destroy residual drug-resistant cells but also provides a sensitive imaging method to monitor micrometastatic disease in common sites of recurrence. Using fluorescence microendoscopy to monitor immunoconjugate activation and micrometastatic disease, we demonstrate these concepts of "tumor-targeted, activatable photoimmunotherapy" in a mouse model of peritoneal carcinomatosis. By introducing targeted activation to enhance tumor selectively in complex anatomical sites, this study offers prospects for catching early recurrent micrometastases and for treating occult disease.
- 26Chilakamarthi, U.; Giribabu, L. Photodynamic Therapy: Past, Present and Future. Chem. Rec. 2017, 17, 775– 802, DOI: 10.1002/tcr.201600121[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtV2ksA%253D%253D&md5=ca59db5a3ecd8874dbd7fcf56131f382Photodynamic Therapy: Past, Present and FutureChilakamarthi, Ushasri; Giribabu, LingamalluChemical Record (2017), 17 (8), 775-802CODEN: CRHEAK; ISSN:1528-0691. (Wiley-VCH Verlag GmbH & Co. KGaA)Though we crossed many milestones in the field of medicine and health care in eradicating some deadly diseases over the past decades, cancer remained a challenge taking the lives of millions of people and having adverse effects on the quality of life of survivors. Chemotherapy and radiotherapy, the two existing major treatment modalities, have severe side effects and patients undergoing these treatments experience unbearable pain. Consequently, clinicians and researchers are working for the alternate treatment regimens, which can provide complete cure with min. or no side effects. To this end, the present review highlights the major advances and future promises of photodynamic therapy, an emerging and promising therapeutic modality for combating cancer. We delve on various important aspects of photodynamic therapy including principle, mechanism of action, brief history and development of photosensitizers from first generation to the existing third generation, delivery strategies, development or suppression of immunity, combination therapy and future prospects.
- 27Juarranz, Á.; Jaén, P.; Sanz-Rodríguez, F.; Cuevas, J.; González, S. Photodynamic Therapy of Cancer. Basic Principles and Applications. Clin. Transl. Oncol. 2008, 10, 148– 154, DOI: 10.1007/s12094-008-0172-2[Crossref], [PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXls1Cisbk%253D&md5=def01f96d817e695b02b79f0f2f4b2a8Photodynamic therapy of cancer. Basic principles and applicationsJuarranz, Angeles; Jaen, Pedro; Sanz-Rodriguez, Francisco; Cuevas, Jesus; Gonzalez, SalvadorClinical & Translational Oncology (2008), 10 (3), 148-154CODEN: CTOLAM; ISSN:1699-048X. (Springer)A review. Photodynamic therapy (PDT) is a minimally invasive therapeutic modality approved for clin. treatment of several types of cancer and non-oncol. disorders. In PDT, a compd. with photosensitizing properties (photosensitizer, PS) is selectively accumulated in malignant tissues. The subsequent activation of the PS by visible light, preferentially in the red region of the visible spectrum (λ≥600 nm), where tissues are more permeable to light, generates reactive oxygen species, mainly singlet oxygen (1O2), responsible for cytotoxicity of neoplastic cells and tumor regression. There are three main mechanisms described by which 1O2 contributes to the destruction of tumors by PDT: direct cellular damage, vascular shutdown and activation of immune response against tumor cells. The advantages of PDT over other conventional cancer treatments are its low systemic toxicity and its ability to selectively destroy tumors accessible to light. Therefore, PDT is being used for the treatment of endoscopically accessible tumors such as lung, bladder, gastrointestinal and gynaecol. neoplasms, and also in dermatol. for the treatment of non-melanoma skin cancers (basal cell carcinoma) and precancerous diseases (actinic keratosis). Photofrin, ALA and its ester derivs. are the main compds. used in clin. trials, though newer and more efficient PSs are being evaluated nowadays.
- 28Huang, P.; Lin, J.; Wang, S.; Zhou, Z.; Li, Z.; Wang, Z.; Zhang, C.; Yue, X.; Niu, G.; Yang, M.; Cui, D.; Chen, X. Photosensitizer-Conjugated Silica-Coated Gold Nanoclusters for Fluorescence Imaging-Guided Photodynamic Therapy. Biomaterials 2013, 34, 4643– 4654, DOI: 10.1016/j.biomaterials.2013.02.063[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXksVOntbg%253D&md5=594d42d07d182e750e5d508177233434Photosensitizer-conjugated silica-coated gold nanoclusters for fluorescence imaging-guided photodynamic therapyHuang, Peng; Lin, Jing; Wang, Shouju; Zhou, Zhijun; Li, Zhiming; Wang, Zhe; Zhang, Chunlei; Yue, Xuyi; Niu, Gang; Yang, Min; Cui, Daxiang; Chen, XiaoyuanBiomaterials (2013), 34 (19), 4643-4654CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Multifunctional theranostics have recently been intensively explored to optimize the efficacy and safety of therapeutic regimens. In this work, a photo-theranostic agent based on chlorin e6 Ce6 photosensitizer-conjugated silica-coated gold nanoclusters [email protected] is strategically designed and prepd. for fluorescence imaging-guided photodynamic therapy PDT. The [email protected] shows the following features: (i) high Ce6 photosensitizer loading; (ii) no non-specific release of Ce6 during its circulation; (iii) significantly enhanced cellular uptake efficiency of Ce6, offering a remarkably improved photodynamic therapeutic efficacy compared to free Ce6; (iv) subcellular characterization of the nanoformula via both the fluorescence of Ce6 and plasmon luminescence of AuNCs; (v) fluorescence imaging-guided photodynamic therapy PDT. This photo-theranostics owns good stability, high water dispersibility and soly., non-cytotoxicity, and good biocompatibility, thus facilitating its biomedical applications, particularly for multi-modal optical, CT and photoacoustic PA imaging-guided PDT or sonodynamic therapy.
- 29Chen, R.; Zhang, L.; Gao, J.; Wu, W.; Hu, Y.; Jiang, X. Chemiluminescent Nanomicelles for Imaging Hydrogen Peroxide and Self-Therapy in Photodynamic Therapy. J. Biomed. Biotechnol. 2011, 2011, 1, DOI: 10.1155/2011/679492
- 30Iranifam, M. Analytical Applications of Chemiluminescence Methods for Cancer Detection and Therapy. TrAC, Trends Anal. Chem. 2014, 59, 156– 183, DOI: 10.1016/j.trac.2014.03.010[Crossref], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFyntbvP&md5=889502e288b2adcf7b0ad25f41a09569Analytical applications of chemiluminescence methods for cancer detection and therapyIranifam, MortazaTrAC, Trends in Analytical Chemistry (2014), 59 (), 156-183CODEN: TTAEDJ; ISSN:0165-9936. (Elsevier B. V.)A review. Cancer is one of the most life-threatening diseases and a leading cause of death and disability for humans. The current state of the art in chemiluminescence (CL) detection methods provides clinicians and researchers interested in oncol. with efficient tools for early detection and accurate diagnosis of cancer. In this context, CL methods are powerful with the capability of detecting cancerous cells and cancer biomarkers, among other applications. Moreover, these methods can aid in increasing the survival chances of cancer patients undergoing chemotherapy and radiotherapy by sensitive monitoring of their progress when undergoing treatment. This article reviews the literature on the applications of CL methods in cancer detection and therapy (e.g., detn. of circulating tumor cells, cancer biomarkers and anticancer drugs, and photodynamic therapy as a light-delivery system and dosimetry tool).
- 31Laptev, R.; Nisnevitch, M.; Siboni, G.; Malik, Z.; Firer, M. A. Intracellular Chemiluminescence Activates Targeted Photodynamic Destruction of Leukaemic Cells. Br. J. Cancer 2006, 95, 189– 196, DOI: 10.1038/sj.bjc.6603241[Crossref], [PubMed], [CAS], Google Scholar31Intracellular chemiluminescence activates targeted photodynamic destruction of leukemic cellsLaptev, R.; Nisnevitch, M.; Siboni, G.; Malik, Z.; Firer, M. A.British Journal of Cancer (2006), 95 (2), 189-196CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)Photodynamic therapy (PDT) involves a two-stage process. A light-absorbing photosensitizer (Ps) is endocytosed and then stimulated by light, inducing transfer of energy to a cytoplasmic acceptor mol. and the generation of reactive oxygen species that initiate damage to cellular membrane components and cytolysis. The expanded use of PDT in the clinic is hindered by the lack of Ps target-cell specificity and the limited tissue penetration by external light radiation. This study demonstrates that bioconjugates composed of transferrin and hematoporphyrin (Tf-Hp), significantly improve the specificity and efficiency of PDT for erythroleukemic cells by a factor of almost seven-fold. Fluorescence microscopy showed that the conjugates accumulate in intracellular vesicles whereas free Hp was mostly membrane bound. Expts. with cells deliberately exposed to Tf-Hp athttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmvFajsbw%253D&md5=21ef59748c36aaedeb938d4f8809b14532Theodossiou, T.; Hothersall, J. S.; Woods, E. A.; Okkenhaug, K.; Jacobson, J.; MacRobert, A. J. Firefly Luciferin-Activated Rose Bengal: In Vitro Photodynamic Therapy by Intracellular Chemiluminescence in Transgenic NIH 3T3 Cells. Cancer Res. 2003, 63, 1818– 1821[PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXivFyns7o%253D&md5=7818a70c9b8d6add3563bac3de176933Firefly Luciferin-activated Rose Bengal: In Vitro Photodynamic Therapy by Intracellular Chemiluminescence in Transgenic NIH 3T3 CellsTheodossiou, Theodossis; Hothersall, John S.; Woods, Elizabeth A.; Okkenhaug, Klaus; Jacobson, Jake; MacRobert, Alexander J.Cancer Research (2003), 63 (8), 1818-1821CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Photodynamic therapy (PDT) of cancer (1 , 2) is a well-established treatment modality that uses light excitation of a photosensitive substance to produce oxygen-related cytotoxic intermediates, such as singlet oxygen or free radicals (3 , 4). Although PDT is advantageous over other forms of cancer treatments because of its limited side effects, its main disadvantage is the poor accessibility of light to more deeply lying malignancies. External light sources such as lasers or lamps can be applied either noninvasively to reach tumors that lie well within the penetration depth of the light or in a minimally invasive fashion (interstitial treatments) in which optical fibers are placed intratumorally through needles. Even with the second approach, light distribution over the tumor is not homogeneous and nonidentified metastatic disease is left untreated. CL, the chem. prodn. of light, is exemplified by firefly light emission mediated by the enzymic (luciferase + ATP) oxidn. of D-luciferin to oxyluciferin (5) . This mobile light source is a targetable alternative to external sources of illumination. Here we show the in vitro photodynamic effect of rose bengal activated by intracellular generation of light, in luciferase-transfected NIH 3T3 murine fibroblasts.33Calixto, G.; Bernegossi, J.; de Freitas, L.; Fontana, C.; Chorilli, M. Nanotechnology-Based Drug Delivery Systems for Photodynamic Therapy of Cancer: A Review. Molecules 2016, 21, 342, DOI: 10.3390/molecules21030342[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28fgs1Chtw%253D%253D&md5=b465d464abfaee5f95d6822157eb9e68Nanotechnology-Based Drug Delivery Systems for Photodynamic Therapy of Cancer: A ReviewCalixto Giovana Maria Fioramonti; Bernegossi Jessica; Chorilli Marlus; de Freitas Laura Marise; Fontana Carla RaquelMolecules (Basel, Switzerland) (2016), 21 (3), 342 ISSN:.Photodynamic therapy (PDT) is a promising alternative approach for improved cancer treatment. In PDT, a photosensitizer (PS) is administered that can be activated by light of a specific wavelength, which causes selective damage to the tumor and its surrounding vasculature. The success of PDT is limited by the difficulty in administering photosensitizers (PSs) with low water solubility, which compromises the clinical use of several molecules. Incorporation of PSs in nanostructured drug delivery systems, such as polymeric nanoparticles (PNPs), solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), gold nanoparticles (AuNPs), hydrogels, liposomes, liquid crystals, dendrimers, and cyclodextrin is a potential strategy to overcome this difficulty. Additionally, nanotechnology-based drug delivery systems may improve the transcytosis of a PS across epithelial and endothelial barriers and afford the simultaneous co-delivery of two or more drugs. Based on this, the application of nanotechnology in medicine may offer numerous exciting possibilities in cancer treatment and improve the efficacy of available therapeutics. Therefore, the aim of this paper is to review nanotechnology-based drug delivery systems for photodynamic therapy of cancer.34Agostinis, P.; Berg, K.; Cengel, K. A.; Foster, T. H.; Girotti, A. W.; Gollnick, S. O.; Hahn, S. M.; Hamblin, M. R.; Juzeniene, A.; Kessel, D.; Korbelik, M.; Moan, J.; Mroz, P.; Nowis, D.; Piette, J.; Wilson, B. C.; Golab, J. Photodynamic Therapy of Cancer: An Update. Ca-Cancer J. Clin. 2011, 61, 250– 281, DOI: 10.3322/caac.20114[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MnkslajtQ%253D%253D&md5=81f4bb716e0dd1967c4819f5593cf109Photodynamic therapy of cancer: an updateAgostinis Patrizia; Berg Kristian; Cengel Keith A; Foster Thomas H; Girotti Albert W; Gollnick Sandra O; Hahn Stephen M; Hamblin Michael R; Juzeniene Asta; Kessel David; Korbelik Mladen; Moan Johan; Mroz Pawel; Nowis Dominika; Piette Jacques; Wilson Brian C; Golab JakubCA: a cancer journal for clinicians (2011), 61 (4), 250-81 ISSN:.Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment.35Zheng, Y.; Yin, G.; Le, V.; Zhang, A.; Lu, Y.; Yang, M.; Fei, Z.; Liu, J. Hypericin-Based Photodynamic Therapy Induces a Tumor-Specific Immune Response and an Effective DC-Based Cancer Immunotherapy. Biochem. Pharmacol. 2014, 1, DOI: 10.1016/j.bcp.2014.01.03636Theodossiou, T. A.; Hothersall, J. S.; De Witte, P. A.; Pantos, A.; Agostinis, P. The Multifaceted Photocytotoxic Profile of Hypericin. Mol. Pharmaceutics 2009, 6, 1775– 1789, DOI: 10.1021/mp900166q[ACS Full Text], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFOiurvM&md5=6707d16cda4a15f52b0681d1e4bfcaa4The Multifaceted Photocytotoxic Profile of HypericinTheodossiou, Theodossis A.; Hothersall, John S.; De Witte, Peter A.; Pantos, Alexandros; Agostinis, PatriziaMolecular Pharmaceutics (2009), 6 (6), 1775-1789CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)A review. Photodynamic therapy (PDT) is an established anticancer treatment employing a phototoxin (photosensitizer), visible light and oxygen. The latter is photochem. converted into reactive oxygen species, which are highly toxic to the cells. Hypericin, a natural pigment of hypericum plants, is prominent among photosensitizers. The unique perylenequinone structure of hypericin is responsible for its intriguing multifaceted photochem. cytotoxicity. The diverse photodynamic action of hypericin targets a range of subcellular organelles most importantly the mitochondria and the endoplasmic reticulum (ER)-Golgi complex. Hypericin exerts its phototoxicity through intricate mechanisms, implicating key proteins, vital enzymes, organelle membranes and changes in cellular homeostasis. This, depending on drug and light administration conditions, leads to cell death, which occurs mainly by the induction of apoptosis and/or necrosis. Cell photosensitization with hypericin is also assocd. with the stimulation of macroautophagy, which may promote cell demise when the apoptotic machinery is defective. Herein, we aim to integrate the most important findings with regard to hypericin photocytotoxicity, into a unified scenario, detailing its potential in cancer photomedicine.37Liu, X.; Jiang, C.; Li, Y.; Liu, W.; Yao, N.; Gao, M.; Ji, Y.; Huang, D.; Yin, Z.; Sun, Z.; Ni, Y.; Zhang, J. Evaluation of Hypericin: Effect of Aggregation on Targeting Biodistribution. J. Pharm. Sci. 2015, 104, 215– 222, DOI: 10.1002/jps.24230[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFWitLzM&md5=dd8b285aaba9bb8c4a8f0a0de81d36b3Evaluation of hypericin. Effect of aggregation on targeting biodistributionLiu, Xuejiao; Jiang, Cuihua; Li, Yue; Liu, Wei; Yao, Nan; Gao, Meng; Ji, Yun; Huang, Dejian; Yin, Zhiqi; Sun, Ziping; Ni, Yicheng; Zhang, JianJournal of Pharmaceutical Sciences (2015), 104 (1), 215-222CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)Hypericin (Hy) has shown great promise as a necrosis-avid agent in cancer imaging and therapy. Given the highly hydrophobic and π-conjugated planarity characteristics, Hy tends to form aggregates. To investigate the effect of aggregation on targeting biodistribution, nonaggregated formulation (Non-Ag), aggregated formulation with overconcd. Hy in DMSO (Ag-DMSO) soln., and aggregated formulation in water soln. (Ag-water) were selected by fluorescence measurement. They were labeled with 131I and evaluated for the necrosis affinity in rat model of reperfused hepatic infarction by gamma counting and autoradiog. The radioactivity ratio of necrotic liver/normal liver was 17.1, 7.9, and 6.4 for Non-Ag, Ag-DMSO, and Ag-water, resp. The accumulation of two aggregated formulations (Ag-DMSO and Ag-water) in organs of mononuclear phagocyte system (MPS) was 2.62 ± 0.22 and 3.96 ± 0.30 %ID/g in the lung, and 1.44 ± 0.29 and 1.51 ± 0.23 %ID/g in the spleen, resp. The biodistribution detected by autoradiog. showed the same trend as by gamma counting. In conclusion, the Non-Ag showed better targeting biodistribution and less accumulation in MPS organs than aggregated formulations of Hy. The two aggregated formulations showed significantly lower and higher accumulation in targeting organ and MPS organs, resp. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.38Ghosh, S.; Banerjee, S.; Sil, P. C. The Beneficial Role of Curcumin on Inflammation, Diabetes and Neurodegenerative Disease: A Recent Update. Food Chem. Toxicol. 2015, 83, 111– 124, DOI: 10.1016/j.fct.2015.05.022[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVWgu7fJ&md5=f8e58560062b009bf029808ca161750aThe beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent updateGhosh, Shatadal; Banerjee, Sharmistha; Sil, Parames C.Food and Chemical Toxicology (2015), 83 (), 111-124CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)The concept of using phytochems. has ushered in a new revolution in pharmaceuticals. Naturally occurring polyphenols (like curcumin, morin, resveratrol, etc.) have gained importance because of their minimal side effects, low cost and abundance. Curcumin (diferuloylmethane) is a component of turmeric isolated from the rhizome of Curcuma longa. Research for more than two decades has revealed the pleiotropic nature of the biol. effects of this mol. More than 7000 published articles have shed light on the various aspects of curcumin including its antioxidant, hypoglycemic, anti-inflammatory and anti-cancer activities. Apart from these well-known activities, this natural polyphenolic compd. also exerts its beneficial effects by modulating different signalling mols. including transcription factors, chemokines, cytokines, tumor suppressor genes, adhesion mols., microRNAs, etc. Oxidative stress and inflammation play a pivotal role in various diseases like diabetes, cancer, arthritis, Alzheimer's disease and cardiovascular diseases. Curcumin, therefore, could be a therapeutic option for the treatment of these diseases, provided limitations in its oral bioavailability can be overcome. The current review provides an updated overview of the metab. and mechanism of action of curcumin in various organ pathophysiologies. The review also discusses the potential for multifunctional therapeutic application of curcumin and its recent progress in clin. biol.39Wikene, K. O.; Hegge, A. B.; Bruzell, E.; Tonnesen, H. H. Formulation and Characterization of Lyophilized Curcumin Solid Dispersions for Antimicrobial Photodynamic Therapy (Apdt): Studies on Curcumin and Curcuminoids LII. Drug Dev. Ind. Pharm. 2015, 41, 969– 977, DOI: 10.3109/03639045.2014.919315[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpt1KltLg%253D&md5=a9bf0fae7d791b8c285e2f66dcac215bFormulation and characterization of lyophilized curcumin solid dispersions for antimicrobial photodynamic therapy (aPDT): studies on curcumin and curcuminoids LIIWikene, Kristine Opsvik; Hegge, Anne Bee; Bruzell, Ellen; Tonnesen, Hanne HjorthDrug Development and Industrial Pharmacy (2015), 41 (6), 969-977CODEN: DDIPD8; ISSN:0363-9045. (Informa Healthcare)Context: Bacterial resistance to antibiotics is increasing and alternative antibacterial treatments like antimicrobial photodynamic therapy (aPDT) are needed. Curcumin is under investigation as a potential photosensitizer in aPDT. Objective: The purpose of this study was to develop rapidly dissolving formulations of curcumin that could photoinactivate both Gram-pos. and Gram-neg. bacteria. Materials and methods: Curcumin solid dispersions with methyl-β-cyclodextrin and hyaluronic acid (HA), hydroxypropyl methylcellulose (HPMC) or both HA and HPMC were prepd. through lyophilization. The lyophilizates were characterized by curcumin drug load [% (wt./wt.)], differential scanning calorimetry, photostability, thermal stability, their ability to form supersatd. solns. and by in vitro photoinactivation of Enterococcus faecalis and Escherichia coli. Results and discussion: The lyophilizates were amorphous solid dispersions with a curcumin drug load in the range of 1.4-5.5% (wt./wt.) depending on the included polymer and the ratio between curcumin and the cyclodextrin. The lyophilizates were photolabile, but thermally stable and dissolved rapidly in contact with water to form supersatd. solns. Selected lyophilizates demonstrated >log 6 redn. of colony forming units/mL of both E. faecalis and E. coli after exposure to low curcumin concns. (0.5-10 μM) and blue light dose (11-16 J/cm2). The high drug load of the lyophilizates, rapid dissoln., ability to form relatively stable supersatd. solns. and the very high phototoxicity towards both E. faecalis and E. coli make these lyophilizates suitable for in vivo aPDT. Conclusions: This treatment with optimized curcumin formulations should be explored as an alternative to topical antibiotics in the treatment of wound infections.40Bernd, A. Visible Light And/Or UVA Offer a Strong Amplification of the Anti-Tumor Effect of Curcumin. Phytochem. Rev. 2014, 13, 183– 189, DOI: 10.1007/s11101-013-9296-2[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXislClt7o%253D&md5=9db0eac5349f398dd3de118fd6abd42aVisible light and/or UVA offer a strong amplification of the anti-tumor effect of curcuminBernd, AugustPhytochemistry Reviews (2014), 13 (1), 183-189CODEN: PRHEBS; ISSN:1568-7767. (Springer)A review. Curcumin, a dietary pigment from the plant Curcuma longa, inhibits cell proliferation and induces apoptosis in different cell lines. The therapeutic benefit is hampered by a very low absorption after trans-dermal or oral application. Therefore, great efforts were undertaken to enhance the effectiveness of curcumin. Recently, it was demonstrated that curcumin offers the described effects also at low concns. (0.2-1 μg/mL) when applied in combination with UVA or visible light. The efficacy of this combination was shown in human epidermal keratinocytes and in a panel of other cell species in vitro as well as in a xenograft tumor model with A431 tumor cells injected s.c. in the flanks of NMRI nude mice in vivo. The treatment of keratinocytes with curcumin and light resulted in the inhibition of cell growth, and in the induction of apoptosis, whereas no toxic cell membrane damage was detectable. The treatment of tumor bearing nude mice with curcumin and visible light resulted in reduced tumor vols., reduced proliferation rates, and the induction of apoptosis in the tumors. On the mol. level inhibition of extracellular regulated kinases 1/2 and epidermal growth factor receptor was obsd. which may aid to inhibition of proliferation and induction of apoptosis. This review covers the experiences of the new combination treatment of human tumors.41Leite, D. P. V.; Paolillo, F. R.; Parmesano, T. N.; Fontana, C. R.; Bagnato, V. S. Effects of Photodynamic Therapy With Blue Light and Curcumin as Mouth Rinse for Oral Disinfection: A Randomized Controlled Trial. Photomed. Laser Surg. 2014, 32, 627– 632, DOI: 10.1089/pho.2014.3805[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVKrsL%252FI&md5=70966da7d6d54531b474cda96eeab749Effects of Photodynamic Therapy with Blue Light and Curcumin as Mouth Rinse for Oral Disinfection: A Randomized Controlled TrialLeite, Diego Portes Vieira; Paolillo, Fernanda Rossi; Parmesano, Thiago Nogueira; Fontana, Carla Raquel; Bagnato, Vanderlei SalvadorPhotomedicine and Laser Surgery (2014), 32 (11), 627-632CODEN: PLDHA8; ISSN:1549-5418. (Mary Ann Liebert, Inc.)Objective: The purpose of this study was to evaluate the effects of the antimicrobial photodynamic therapy (a-PDT) with blue light and curcumin on oral disinfection during the 2 h after treatment. Background data: a-PDT is a technique that can potentially affect the viability of bacterial cells, with selective action targeting only areas with photosensitizer accumulation. Materials and methods: A randomized controlled trial was undertaken. Twenty-seven adults were randomly divided into three groups: (1) the PDT group, which was treated with the drug, curcumin, and blue light (n=9); (2) the light group, which was treated only with the blue light, and no drug (n=9) and; (3) the curcumin group, which was treated only with the drug, curcumin, and no light (n=9). The irradn. parameters were: blue light-emitting diode (LED) illumination (455±30 nm), 400 mW of av. optical power, 5 min of application, illumination area of 0.6 cm2, 600 mW/cm2 of intensity, and 200 J/cm2 of fluence. A curcumin concn. of 30 mg/L was used. The saliva samples were collected for bacterial counts at baseline and after the exptl. phases (immediately after treatment, and 1 and 2 h after treatment). Serial dilns. were performed, and the resulting samples were cultured on blood agar plates in microaerophilic conditions. The no. of colony-forming units (CFU) was detd. Results: The PDT group showed a significant redn. of CFU immediately after treatment (post-treatment) with PDT (5.71±0.48, p=0.001), and 1 h (5.14±0.92, p=0.001) and 2 h (5.35±0.76, p=0.001) after treatment, compared with pretreatment (6.61±0.82). There were no significant changes for the light group. The curcumin group showed a significant increase of CFU 1 h after treatment (6.77±0.40, p=0.02) compared with pretreatment (5.57±0.91) falling to baseline values at 2 h after treatment (5.58±0.70). Conclusions: The PDT group showed significant difference in microbial redn. (p<0.05) compared with both the light and curcumin groups until 2 h post-treatment. The new blue LED device for PDT using curcumin may be used for redn. of salivary microorganisms, leading to overall disinfection of the mouth (e.g., mucosa, tongue, and saliva), but new protocols should be explored.42Li, T.; Hou, X.; Deng, H.; Zhao, J.; Huang, N.; Zeng, J.; Chen, H.; Gu, Y. Liposomal Hypocrellin B as a Potential Photosensitizer for Age-Related Macular Degeneration: Pharmacokinetics, Photodynamic Efficacy, and Skin Phototoxicity in Vivo. Photochem. Photobiol. Sci. 2015, 14, 972– 981, DOI: 10.1039/C4PP00412D[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXktVCru70%253D&md5=8b2e424c8fe901ce286a08c7142d18f9Liposomal hypocrellin B as a potential photosensitizer for age-related macular degeneration: pharmacokinetics, photodynamic efficacy, and skin phototoxicity in vivoLi, Tinghui; Hou, Xiaobin; Deng, Hong; Zhao, Jingquan; Huang, Naiyan; Zeng, Jing; Chen, Hongxia; Gu, YingPhotochemical & Photobiological Sciences (2015), 14 (5), 972-981CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)Photodynamic therapy (PDT) has been successfully implemented as a treatment for wet age-related macular degeneration (AMD), but very few photosensitizers have been developed for clin. use. Herein, we describe a novel formulation of liposomal hypocrellin B (LHB) that was prepd. by high-pressure homogenization. The encapsulation efficiency and PDT efficacy in vitro of this new prepn. were found to remain nearly const. over 1 yr. Moreover, LHB is rapidly cleared from the blood, with a half-life of 2.319 ± 0.462 h and a very low serum concn. at 24 h after injection. Testing in a rat model of choroidal neovascularization (CNV) showed that leakage of blood vessels in CNV lesions was significantly reduced when LHB PDT was given at a dose of 1 mg kg-1 along with yellow laser irradn.; the damage to the collateral retina and the retinal pigment epithelium was minimal. Skin phototoxicity assays showed that only two of the 200 mice given a 4 mg per kg dose of LHB experienced an inflammatory reaction in the auricle irradiated at 24 h after dosing. These data collectively indicate that LHB may be a safe and effective photosensitizer for vascular-targeted PDT of AMD.43Zhenjun, D.; Lown, J. W. Hypocrellins and Their Use in Photosensitization. Photochem. Photobiol. 1990, 52, 609– 616, DOI: 10.1111/j.1751-1097.1990.tb01807.x[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3M7jsVamsA%253D%253D&md5=7e9e59d181a240b48b37f8227217c899Hypocrellins and their use in photosensitizationZhenjun D; Lown J WPhotochemistry and photobiology (1990), 52 (3), 609-16 ISSN:0031-8655.Hypocrellins A and B are pigments which are isolated from parasitic fungi Hypocrella bambuase (B. et Br) sacc. and Shiraia bambusicola P. Heen found in the People's Republic of China (P.R.C.) and Sri Lanka respectively. These agents, which belong to the general class of perylene quinonoid pigments, have a long history of traditional medicinal agents especially in the P.R.C. Recently their marked photosensitizing properties have been established and exploratory studies initiated. This effort has led to the realization of the potential of the hypocrellins for the photodynamic therapy of tumors. The review summarizes the chemical and photophysical properties of the hypocrellins and their derivatives as well as studies on photosensitization to date at the molecular, cellular and in vivo levels, and their prospects as PDT agents.44Makdoumi, K.; Bäckman, A.; Mortensen, J.; Crafoord, S. Evaluation of Antibacterial Efficacy of Photo-Activated Riboflavin Using Ultraviolet Light (UVA). Graefe's Arch. Clin. Exp. Ophthalmol. 2010, 248, 207– 212, DOI: 10.1007/s00417-009-1231-2[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtVagsQ%253D%253D&md5=3e7abe61dbe79d17c856cc8ae80cfc66Evaluation of antibacterial efficacy of photo-activated riboflavin using ultraviolet light (UVA)Makdoumi, Karim; Baeckman, Anders; Mortensen, Jes; Crafoord, SvenGraefe's Archive for Clinical and Experimental Ophthalmology (2010), 248 (2), 207-212CODEN: GACODL; ISSN:0721-832X. (Springer)Background: To evaluate the antibacterial efficacy of photo-activated riboflavin using UV A (UVA) on three bacterial strains commonly detected in keratitis. Methods: Three bacterial strains (Staphylococcus epidermidis, Staphylococcus aureus and Pseudomonas aeruginosa) were cultured on blood/hematin-agar plates and dispersed in PBS. Dispersion was done of 10 μl of bacterial stock-solns. in 90 μl of RPMI, where different riboflavin molarities had been added, to achieve a bacterial concn. of 1-4 × 10 4/mL. Riboflavin end molarities before illumination were 0, 100, 200, 300 and 400 μM. Each soln. had a neg. control. The solns. were illuminated with UVA (365 nm) for 30 min (5.4 J/cm2) and then continued for a total time of 60 min (10.8 J/cm2). A count of CFU was conducted after incubation and results compared. Results: In all tested strains, a slight decrease of bacteria was seen when exposed to UV for 30 min. A doubling of the UV dose showed a marked decrease of bacterial count in all bacteria tested. The combination of UV and riboflavin showed a more extensive redn. of CFU, confirming an interaction effect between UV and riboflavin. Conclusion: Riboflavin photo-activation using UVA (365 nm) can achieve an extensive eradication of bacteria, and the combination is more potent in reducing bacterial no. than UV alone.45Ettinger, A.; Miklauz, M. M.; Bihm, D. J.; Maldonado-Codina, G.; Goodrich, R. P. Preparation of Cryoprecipitate from Riboflavin and UV Light-Treated Plasma. Transfus. Apher. Sci. 2012, 46, 153– 158, DOI: 10.1016/j.transci.2012.01.004[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38zhslalsg%253D%253D&md5=03b3cf522e68a6ccd4b4f8d70224b585Preparation of cryoprecipitate from riboflavin and UV light-treated plasmaEttinger Anna; Miklauz Meghan M; Bihm David J; Maldonado-Codina Gabriela; Goodrich Raymond PTransfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis (2012), 46 (2), 153-8 ISSN:1473-0502.BACKGROUND AND OBJECTIVES: The Mirasol® pathogen reduction technology system for plasma is based on a riboflavin and UV light treatment process resulting in pathogen inactivation due to irreversible, photochemically induced damage of nucleic acids. This study was undertaken to evaluate the possibility of making pathogen reduced cryoprecipitate from riboflavin and UV light- treated plasma that meets the quality requirements specified by UK and European guidelines for untreated cryoprecipitate. MATERIALS AND METHODS: Cryoprecipitate was made from riboflavin and UV light-treated plasma. Plasma units were thawed over a 20 h period at 4°C, and variable centrifugation settings (from 654 g for 2 min to 5316 g for 6 min) were applied to identify the optimal centrifugation condition. Plasma proteins in cryoprecipitate units were characterized on a STA Compact, Diagnostica STAGO and Siemens BCS analyzer. RESULTS: Neither the centrifugation speed or time appeared to have an effect on the quality of the final cryoprecipitate product; however the initial solubilization of the cryoprecipitate product was found to be easier at the lower centrifugation setting (654 g for 2 min). Cryoprecipitate units prepared from Mirasol-treated plasma demonstrated protein levels that were less than levels in untreated products, but were on average 93 IU/unit, 262 mg/unit and 250 IU/unit for FVIII, fibrinogen and von Willebrand ristocetin cofactor activity, respectively. CONCLUSION: Cryoprecipitate products prepared from Mirasol-treated plasma using a centrifugation method contain levels of fibrinogen, FVIII and von Willebrand ristocetin cofactor activity, that meet both the European and UK guidelines for untreated cryoprecipitate. Flexibility in centrifugation conditions should allow blood banks to use their established centrifugation settings to make cryoprecipitate from Mirasol-treated plasma.46Papaioannou, L.; Miligkos, M.; Papathanassiou, M. Corneal Collagen Cross-Linking for Infectious Keratitis: A Systematic Review and Meta-Analysis. Cornea 2016, 35, 62– 71, DOI: 10.1097/ICO.0000000000000644[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28zmtFersA%253D%253D&md5=ed7151382dd7de05a81eb72f3d1d4195Corneal Collagen Cross-Linking for Infectious Keratitis: A Systematic Review and Meta-AnalysisPapaioannou Lamprini; Miligkos Michael; Papathanassiou MiltiadisCornea (2016), 35 (1), 62-71 ISSN:.PURPOSE: To assess the efficacy of corneal collagen cross-linking (CXL) in the management of infectious keratitis. METHODS: Comprehensive literature search was performed in MEDLINE/PubMed and Cochrane Central Register of Controlled Trials using combinations of the following search terms: "corneal collagen cross linking" or "photoactivated riboflavin" or "UVA light and riboflavin" and "infectious keratitis" or "corneal ulcer." Last search was on March 19, 2015. Extracted data from individual studies were summarized and summary proportions of eyes healed and complications for different subgroups were estimated. RESULTS: Twenty-five studies were included (2 randomized controlled trials, 13 case series, and 10 case reports) with a total of 210 eyes of 209 patients, of which 175 eyes underwent CXL. Causative microorganisms were bacteria, fungi, acanthamoeba, and Herpes simplex virus in 96, 32, 11, and 2 cases, respectively. Coinfections were present in 13 and cause was inconclusive in 21 cases. Sixteen of 175 eyes received no additional antibiotics, whereas 159 underwent CXL as an adjunct to antimicrobial treatment. Proportion of eyes healed with CXL was 87.2% (95% confidence interval (CI), 81.9%, 91.8%). For bacterial keratitis, the proportion of eyes healed was 85.7% (95% CI, 78.5%, 91.7%), whereas 10/11 and 25/32 eyes with acanthamoeba and fungal keratitis, respectively, were healed (available data not sufficient to provide a valid proportion analysis). Treatment resulted in corneal melting and tectonic keratoplasty in both Herpes simplex virus cases. CONCLUSIONS: CXL seems promising in the management of infectious keratitis, excluding viral infections. However, more randomized controlled trials are required to assess its efficacy.47Maisch, T.; Eichner, A.; Späth, A.; Gollmer, A.; König, B.; Regensburger, J.; Bäumler, W. Fast and Effective Photodynamic Inactivation of Multiresistant Bacteria by Cationic Riboflavin Derivatives. PLoS One 2014, 9, e111792, DOI: 10.1371/journal.pone.0111792[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtleks78%253D&md5=03002bb88b715070b6ed2f7b214e9f73Fast and effective photodynamic inactivation of multiresistant bacteria by cationic riboflavin derivativesMaisch, Tim; Eichner, Anja; Spaeth, Andreas; Gollmer, Anita; Koenig, Burkhard; Regensburger, Johannes; Baeumler, WolfgangPLoS One (2014), 9 (12), e111792/1-e111792/18, 18 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Photodynamic inactivation of bacteria (PIB) proves to be an addnl. method to kill pathogenic bacteria. PIB requires photosensitizer mols. that effectively generate reactive oxygen species like singlet oxygen when exposed to visible light. To allow a broad application in medicine, photosensitizers should be safe when applied in humans. Substances like vitamin B2, which are most likely safe, are known to produce singlet oxygen upon irradn. In the present study, we added pos. charges to flavin derivs. to enable attachment of these mols. to the neg. charged surface of bacteria. Two of the synthesized flavin derivs. showed a high quantum yield of singlet oxygen of approx. 75%. Multidrug resistant bacteria like MRSA (Methicillin resistant Staphylococcus aureus), EHEC (enterohemorrhagic Escherichia coli), Pseudomonas aeruginosa, and Acinetobacter baumannii were incubated with these flavin derivs. in vitro and were subsequently irradiated with visible light for seconds only. Singlet oxygen prodn. in bacteria was proved by detecting its luminescence at 1270 nm. After irradn., the no. of viable bacteria decreased up to 6 log10 steps depending on the concn. of the flavin derivs. and the light dosimetry. The bactericidal effect of PIB was independent of the bacterial type and the corresponding antibiotic resistance pattern. In contrast, the photosensitizer concn. and light parameters used for bacteria killing did not affect cell viability of human keratinocytes (therapeutic window). Multiresistant bacteria can be safely and effectively killed by a combination of modified vitamin B2 mols., oxygen and visible light, whereas normal skin cells survive. Further work will include these new photosensitizers for topical application to decolonize bacteria from skin and mucosa.48Wainwright, M.; Crossley, K. B. Methylene Blue - a Therapeutic Dye for All Seasons?. J. Chemother. 2002, 14, 431– 443, DOI: 10.1179/joc.2002.14.5.431[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XpsVyrsbc%253D&md5=090d09b1bcf57306634e09ecd6c513efMethylene blue - a therapeutic dye for all seasons?Wainwright, M.; Crossley, K. B.Journal of Chemotherapy (Firenze, Italy) (2002), 14 (5), 431-443CODEN: JCHEEU; ISSN:1120-009X. (E.I.F.T. srl)A review. Since it was first synthesized in 1876, Methylene Blue (MB) has found uses in many different areas of clin. medicine, ranging from dementia to cancer chemotherapy. In addn., MB formed the basis of antimicrobial chemotherapy - particularly in the area of antimalarials - and eventually led to the discovery of the neuroleptic drug families. More recently, the photosensitizing potential of MB and its congeners has been recognized, and these are being applied in various antimicrobial fields, esp. that of blood disinfection. The range of activities of MB is due to the combination of its simple chem. structure and facility for oxidn.-redn. reactions in situ.49Tseng, S. P.; Hung, W. C.; Chen, H. J.; Lin, Y. T.; Jiang, H. S.; Chiu, H. C.; Hsueh, P. R.; Teng, L. J.; Tsai, J. C. Effects of Toluidine Blue O (Tbo)-Photodynamic Inactivation on Community-Associated Methicillin-Resistant Staphylococcus Aureus Isolates. J. Microbiol. Immunol. Infect. 2017, 50, 46– 54, DOI: 10.1016/j.jmii.2014.12.007[Crossref], [PubMed], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1eisLk%253D&md5=562bc22fbde3d28bc63b4ee4c25a2397Effects of toluidine blue O (TBO)-photodynamic inactivation on community-associated methicillin-resistant Staphylococcus aureus isolatesTseng, Sung-Pin; Hung, Wei-Chun; Chen, Hsiao-Jan; Lin, Yu-Tzu; Jiang, Hung-Sih; Chiu, Hao-Chieh; Hsueh, Po-Ren; Teng, Lee-Jene; Tsai, Jui-ChangJournal of Microbiology, Immunology and Infection (2017), 50 (1), 46-54CODEN: JMIIFG; ISSN:1995-9133. (Elsevier Taiwan LLC)Community-assocd. methicillin-resistant Staphylococcus aureus (CA-MRSA) was recognized as a leading pathogen and has been shown to be genetically different from the health care-assocd. MRSA (HA-MRSA). Photodynamic therapy (PDT) is considered a potential alternative method for the treatment of resistant bacterial infections, but the effect of PDT on CA-MRSA is unknown. The purpose of this study was to compare the bactericidal effects of toluidine blue O (TBO) on CA-MRSA and HA-MRSA and investigate the photodynamic inactivation effects of TBO (TBO-PDI) against bacterial virulence factors.TBO-PDI effects were detd. by measuring the survival fractions for four strains and bactericidal activities for 26 CA-MRSA isolates and 26 HA-MRSA isolates. The influences of TBO-PDI on DNA fragmentation and the activities of protease, lipase, staphylococcal α-hemolysin, and enterotoxin were studied.TBO-PDI has effective bactericidal activity against both CA- and HA-MRSA. However, the bactericidal activity of TBO-PDI was significantly higher against HA-MRSA than CA-MRSA isolates. In addn., TBO-PDI treatment using a sublethal TBO concn. led to reduced prodn. of several virulence factors, including protease, lipase, staphylococcal α-hemolysin, and enterotoxin.Although TBO-PDI is slightly less effective against CA-MRSA than HA-MRSA isolates, TBO-PDI could reduce the prodn. of virulence factors at a sublethal TBO concn., which would be beneficial for treating CA-MRSA infections.50Tardivo, J. P.; Adami, F.; Correa, J. A.; Pinhal, M. A. S.; Baptista, M. S. A Clinical Trial Testing the Efficacy of PDT in Preventing Amputation in Diabetic Patients. Photodiagn. Photodyn. Ther. 2014, 11, 342– 350, DOI: 10.1016/j.pdpdt.2014.04.007[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cjhsVyjsA%253D%253D&md5=512e37c1f471177c72e63380746ace58A clinical trial testing the efficacy of PDT in preventing amputation in diabetic patientsTardivo Joao Paulo; Adami Fernando; Correa Joao Antonio; Pinhal Maria Aparecida S; Baptista Mauricio SPhotodiagnosis and photodynamic therapy (2014), 11 (3), 342-50 ISSN:.The feet of diabetic patients continue to be an unsolved problem in medicine. Uncontrolled neuropathy, ulceration and infection usually lead to amputation and presently there is no effective and reliable method that can be used to provide an efficient cure. Overall improvement in the salvage strategies, based on comprehensive pre-clinical evaluation, debridement, antibiotic therapy and follow up, has shown improvements in certain hospital settings, but the general picture for patients with diabetic foot is to have some sort of amputation, especially in underserved populations. It is clearly necessary to develop novel treatment strategies for this worldwide health problem. Photodynamic therapy (PDT) is a treatment modality that uses light to generate in situ reactive oxygen species, which can cause cell death. PDT can be used to treat several diseases, including foot infections that do not respond well to antibiotic therapy. There are several characteristics of PDT that make it potentially ideal to treat diabetic feet: the photosensitizer is non-toxic in the dark, but after illumination it becomes a very efficient antimicrobial agent with topical use, and it can regenerate small bones, such as the phalanges. However, PDT is still not used in clinical practice to treat diabetic feet. Therefore, we decided to perform a clinical study to prove that PDT is an effective method to avoid amputation of infected diabetic feet. An inexpensive PDT protocol was developed and applied to 18 patients with osteomyelitis, classified as Grade 3 on the Wagner scale. Only one of these patients suffered amputation. At least two of them were cured from resistant bacteria strains without intravenous antibiotic therapy. In the control group of 16 patients, all of them ended up suffering amputation. The rate of amputation in the PDT group was 0.029 times the rate in the control group and the difference is clearly statistically significant (p=0.002).51Graciano, T. B.; Coutinho, T. S.; Cressoni, C. B.; Freitas, C. de P.; Pierre, M. B. R.; de Lima Pereira, S. A.; Shimano, M. M.; Cristina da Cunha Frange, R.; Garcia, M. T. J. Using Chitosan Gels as a Toluidine Blue O Delivery System for Photodynamic Therapy of Buccal Cancer: In Vitro and in Vivo Studies. Photodiagn. Photodyn. Ther. 2015, 12, 98– 107, DOI: 10.1016/j.pdpdt.2014.11.003[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVSiu7jP&md5=14e5024b1db511500cf14af177627f89Using chitosan gels as a toluidine blue O delivery system for photodynamic therapy of buccal cancer: In vitro and in vivo studiesGraciano, Thierllen Barroso; Coutinho, Tatielle Soares; Cressoni, Camila Beatriz; Freitas, Cristhiane de Paula; Pierre, Maria Bernadete Riemma; de Lima Pereira, Sanivia Aparecida; Shimano, Marcos Massao; Cristina da Cunha Frange, Renata; Garcia, Maria Teresa JunqueiraPhotodiagnosis and Photodynamic Therapy (2015), 12 (1), 98-107CODEN: PPTHBF; ISSN:1572-1000. (Elsevier B.V.)Photodynamic therapy (PDT) is an emerging treatment that has demonstrated potential for the clin. treatment of buccal cancer. It is based on the photoactivation of a photosensitizer (PS) when irradiated by light at a specific wavelength. The light-excited PS generates reactive oxygen species that cause the destruction of tumor cells by apoptosis or necrosis. Toluidine Blue O (TBO) is a PS that has shown potential for PDT in cancer treatment. However, saliva and mech. activities quickly remove the PS from the surface of the buccal mucosa. Therefore, the bioavailability of PS at the surface of target tissues is reduced. The aim of this study was to evaluate the potential of chitosan (CH) gels in TBO delivery to buccal tissue. CH gels were obtained at different concns. and their physico-chem. properties (pH and rheol.), mucoadhesion, in vitro release profile, in vivo retention and in vivo efficacy by the ability to induce cell apoptosis were evaluated. CH-based mucoadhesive gels optimized the release and adherence of prepns. at the target site. Specifically, 4% (wt./wt.) CH gel showed adequate properties for buccal use, such as pH value, mucoadhesion, pseudoplastic behavior, extended release, minimal permeation and higher TBO retention by the mucosa. In vivo studies showed the potential of the gel to enhance TBO retention and induce cell apoptosis after laser irradn.4% (wt./wt.) CH based mucoadhesive gel can be explored as a TBO delivery system in the PDT of oral cancer.52Costa, A. C. B. P.; Rasteiro, V. M. C.; Pereira, C. A.; Rossoni, R. D.; Junqueira, J. C.; Jorge, A. O. C. The Effects of Rose Bengal- and Erythrosine-Mediated Photodynamic Therapy on Candida Albicans. Mycoses 2012, 55, 56– 63, DOI: 10.1111/j.1439-0507.2011.02042.x[Crossref], [PubMed], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivFOkt74%253D&md5=731f0333f2ea4e9c200fc9400a27a172The effects of rose bengal- and erythrosine-mediated photodynamic therapy on Candida albicansCosta, Anna Carolina Borges Pereira; Rasteiro, Vanessa Maria Campos; Pereira, Cristiane Aparecida; Rossoni, Rodnei Dennis; Junqueira, Juliana Campos; Jorge, Antonio Olavo CardosoMycoses (2012), 55 (1), 56-63CODEN: MYCSEU; ISSN:0933-7407. (Wiley-Blackwell)The aim of this study was to evaluate the effects of photodynamic therapy (PDT) using rose bengal or erythrosine with light emitting diode (LED) on Candida albicans planktonic cultures and biofilms. Seven C. albicans clin. strains and one std. strain (ATCC 18804) were used. Planktonic cultures and biofilms of each C. albicans strain were submitted to the following exptl. conditions: (a) treatment with rose bengal and LED (RB+L+); (b) treatment with erythrosine and LED (E+L+); and (c) control group, without LED irradn. or photosensitizer treatment (P-L-). After irradn. of the planktonic cultures and biofilms, the cultures were seeded onto Sabouraud dextrose agar (37 °C at 48 h) for counting of colony-forming units (CFU ml-1) followed by posterior ANOVA and Tukey's test analyses (P < 0.05). The biofilms were analyzed using SEM (SEM). The results revealed a significant redn. of planktonic cultures (3.45 log10 and 1.97 log10) and of biofilms (<1 log10) for cultures that were subjected to PDT mediated using either erythrosine or rose bengal, resp. The SEM data revealed that the PDT was effective in reducing and destroying of C. albicans blastoconidia and hyphae. The results show that erythrosine- and rose bengal-mediated PDT with LED irradn. is effective in treating C. albicans.53Xu, N.; Yao, M.; Farinelli, W.; Hajjarian, Z.; Wang, Y.; Redmond, R. W.; Kochevar, I. E. Light-Activated Sealing of Skin Wounds. Lasers Surg. Med. 2015, 47, 17– 29, DOI: 10.1002/lsm.22308[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MzgtF2ksg%253D%253D&md5=95faf4def4ea78fed936012e292511c2Light-activated sealing of skin woundsXu Nan; Yao Min; Farinelli William; Hajjarian Zeinab; Wang Ying; Redmond Robert W; Kochevar Irene ELasers in surgery and medicine (2015), 47 (1), 17-29 ISSN:.BACKGROUND AND OBJECTIVES: We have developed a light-activated technology for rapidly sealing skin surgical wounds called photochemical tissue bonding (PTB). The goals of this study were to evaluate parameters influencing PTB in order to optimize its clinical efficacy and to determine whether PTB can be used to seal wounds in moderately to highly pigmented skin. STUDY DESIGN/MATERIALS AND METHODS: Application of Rose Bengal (RB) followed by exposure to 532 nm was used to seal linear incisions (1.5 mm deep, 2 cm long) in lightly pigmented (Yorkshire) and darkly pigmented (Yucatan) swine skin. The force required to open the seal (the bonding strength) was measured by in situ tensiometry. Reflectance spectra, epidermal transmission spectra, and histology were used to characterize the skin. The relationships of RB concentration and fluence to bonding strength were established in Yorkshire skin. Surface temperature was measured during irradiations and cooling was used while sealing incisions in Yucatan skin. Monte Carlo simulations were carried out to estimate the effect of epidermal melanin on the power absorbed in the dermis at the incision interface. RESULTS: The lowest fluence, 25 J/cm(2), delivered at an irradiance of 0.5 W/cm(2) substantially increased the bonding strength (∼ 10-fold) compared to controls in Yorkshire swine skin. Increasing the fluence to 100 J/cm(2) enhanced bonding strength by a further 1.5-fold. Application of 0.1% RB for 2 minutes produced the greatest bonding strength using 100 J/cm(2) and limited the penetration of RB to an ∼ 50 μm band on the dermal incision wall. Reflectance spectra indicated that Yorkshire skin had minimal melanin and that Yucatan skin was a good model for highly pigmented human skin. In Yucatan skin, the bonding strength increased 1.7-fold using 0.1% RB and 200 J/cm(2) at 1.5 W/cm(2) with cooling and epinephrine. Monte Carlo simulation indicated that absorption of 532 nm light by epidermal melanin in dark skin decreased the power absorbed along the incision in the dermis by a factor of 2.7. CONCLUSIONS: These results suggest that in lightly pigmented skin the PTB treatment time can be shortened without compromising the bonding strength. Sealing incisions using PTB in moderately and highly pigmented skin will require a careful balance of irradiance and cooling.54Panzarini, E.; Inguscio, V.; Fimia, G. M.; Dini, L. Rose Bengal Acetate PhotoDynamic Therapy (RBAc-PDT) Induces Exposure and Release of Damage-Associated Molecular Patterns (DAMPs) in Human HeLa Cells. PLoS One 2014, 9, e105778, DOI: 10.1371/journal.pone.0105778[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1ygu7fK&md5=d5156eca1fe2d4a407baa75746cb2923Rose Bengal acetate photodynamic therapy (RBAc-PDT) induces exposure and release of damage-associated molecular patterns (DAMPs) in human HeLa cellsPanzarini, Elisa; Inguscio, Valentina; Fimia, Gian Maria; Dini, LucianaPLoS One (2014), 9 (8), e105778/1-e105778/12, 12 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)The new concept of Immunogenic Cell Death (ICD), assocd. with Damage Assocd. Mol. Patterns (DAMPs) exposure and/or release, is recently becoming very appealing in cancer treatment. In this context, PhotoDynamic Therapy (PDT) can give rise to ICD and to immune response upon dead cells removal. The list of PhotoSensitizers (PSs) able to induce ICD is still short and includes Photofrin, Hypericin, Foscan and 5-ALA. The goal of the present work was to investigate if Rose Bengal Acetate (RBAc), a powerful PS able to trigger apoptosis and autophagy, enables photosensitized HeLa cells to expose and/or release pivotal DAMPs, i.e. ATP, HSP70, HSP90, HMGB1, and calreticulin (CRT), that characterize ICD. We found that apoptotic HeLa cells after RBAc-PDT exposed and released, early after the treatment, high amt. of ATP, HSP70, HSP90 and CRT; the latter was distributed on the cell surface as uneven patches and co-exposed with ERp57. Conversely, autophagic HeLa cells after RBAc-PDT exposed and released HSP70, HSP90 but not CRT and ATP. Exposure and release of HSP70 and HSP90 were always higher on apoptotic than on autophagic cells. HMGB1 was released concomitantly to secondary necrosis (24 h after RBAc-PDT). Phagocytosis assay suggests that CRT is involved in removal of RBAc-PDT generated apoptotic HeLa cells. Altogether, our data suggest that RBAc has all the prerequisites (i.e. exposure and/or release of ATP, CRT, HSP70 and HSP90), that must be verified in future vaccination expts., to be considered a good PS candidate to ignite ICD. We also showed tha CRT is involved in the clearance of RBAc photokilled HeLa cells. Interestingly, RBAc-PDT is the first cancer PDT protocol able to induce the translocation of HSP90 and plasma membrane co-exposure of CRT with ERp57.55Boens, N.; Leen, V.; Dehaen, W. Fluorescent Indicators Based on Bodipy. Chem. Soc. Rev. 2012, 41, 1130– 1172, DOI: 10.1039/C1CS15132K[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xns1ygsA%253D%253D&md5=98531e55ea0e8130360135a0fa4deb59Fluorescent indicators based on BODIPYBoens, Noel; Leen, Volker; Dehaen, WimChemical Society Reviews (2012), 41 (3), 1130-1172CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. This crit. review covers the advances made using the 4-bora-3a,4a-diaza-s-indacene (BODIPY) scaffold as a fluorophore in the design, synthesis and application of fluorescent indicators for pH, metal ions, anions, biomols., reactive oxygen species, reactive nitrogen species, redox potential, chem. reactions and various phys. phenomena. The sections of the review describing the criteria for rational design of fluorescent indicators and the math. expressions for analyzing spectrophotometric and fluorometric titrns. are applicable to all fluorescent probes (206 refs.).56Kamkaew, A.; Lim, S. H.; Lee, H. B.; Kiew, L. V.; Chung, L. Y.; Burgess, K. BODIPY Dyes in Photodynamic Therapy. Chem. Soc. Rev. 2013, 42, 77– 88, DOI: 10.1039/C2CS35216H[Crossref], [PubMed], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslKrurbJ&md5=69fddf735bafa0b2b33a70835af1430fBODIPY dyes in photodynamic therapyKamkaew, Anyanee; Lim, Siang Hui; Lee, Hong Boon; Kiew, Lik Voon; Chung, Lip Yong; Burgess, KevinChemical Society Reviews (2013), 42 (1), 77-88CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. BODIPY dyes tend to be highly fluorescent, but their emissions can be attenuated by adding substituents with appropriate oxidn. potentials. Substituents like these have electrons to feed into photoexcited BODIPYs, quenching their fluorescence, thereby generating relatively long-lived triplet states. Singlet oxygen is formed when these triplet states interact with 3O2. In tissues, this causes cell damage in regions that are illuminated, and this is the basis of photodynamic therapy (PDT). The PDT agents that are currently approved for clin. use do not feature BODIPYs, but there are many reasons to believe that this situation will change. This review summarizes the attributes of BODIPY dyes for PDT, and in some related areas.57Segado, M.; Reguero, M. Mechanism of the Photochemical Process of Singlet Oxygen Production by Phenalenone. Phys. Chem. Chem. Phys. 2011, 13, 4138, DOI: 10.1039/c0cp01827a[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitVSlu7o%253D&md5=9401ff6f2fc4d817148a325d282a5959Mechanism of the photochemical process of singlet oxygen production by phenalenoneSegado, Mireia; Reguero, MarPhysical Chemistry Chemical Physics (2011), 13 (9), 4138-4148CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)Phenalenone (PN) is a very efficient singlet oxygen sensitizer in a wide range of solvents. This work uses ab initio quantum chem. calcns. (CASSCF/CASPT2 protocol) to study the mechanism for populating the triplet state of PN responsible for this reaction, the 3(π-π*) state. To describe in detail this reaction path, the singlet and triplet low-lying excited states of PN have been studied, the crit. points of the potential energy surfaces corresponding to these states located and the vertical and adiabatic energies calcd. Our results show that, after the initial population of the S2 excited state of (π-π*) character, the system undergoes an internal conversion to the 1(n-π*) state. After populating the dark S1 state, the system relaxes to the 1(n-π*) min., but rapidly populates the triplet manifold through a very efficient intersystem crossing to the 3(π-π*) state. Although the population of the min. of this triplet state is strongly favored, a conical intersection with the 3(n-π*) surface opens an internal conversion channel to this state, a path accessible only at high temps. Radiationless deactivation processes are ruled out on the basis of the high-energy barriers found for the crossings between the excited states and the ground state. Our computational results satisfactorily explain the exptl. findings and are in very good agreement with the exptl. data available. In the case of the frequency of fluorescence, this is the first time that these data have been theor. predicted in good agreement with the exptl. results.58Cieplik, F.; Späth, A.; Regensburger, J.; Gollmer, A.; Tabenski, L.; Hiller, K. A.; Bäumler, W.; Maisch, T.; Schmalz, G. Photodynamic Biofilm Inactivation by SAPYR - an Exclusive Singlet Oxygen Photosensitizer. Free Radical Biol. Med. 2013, 65, 477– 487, DOI: 10.1016/j.freeradbiomed.2013.07.031[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFylsb7P&md5=d4110d5f0ee834b47d8ae17223091d27Photodynamic biofilm inactivation by SAPYR-An exclusive singlet oxygen photosensitizerCieplik, Fabian; Spaeth, Andreas; Regensburger, Johannes; Gollmer, Anita; Tabenski, Laura; Hiller, Karl-Anton; Baeumler, Wolfgang; Maisch, Tim; Schmalz, GottfriedFree Radical Biology & Medicine (2013), 65 (), 477-487CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)Prevention and control of biofilm-growing microorganisms are serious problems in public health due to increasing resistances of some pathogens against antimicrobial drugs and the potential of these microorganisms to cause severe infections in patients. Therefore, alternative approaches that are capable of killing pathogens are needed to supplement std. treatment modalities. One alternative is the photodynamic inactivation of bacteria (PIB). The lethal effect of PIB is based on the principle that visible light activates a photosensitizer, leading to the formation of reactive oxygen species, e.g., singlet oxygen, which induces phototoxicity immediately during illumination. SAPYR is a new generation of photosensitizers. Based on a 7-perinaphthenone structure, it shows a singlet oxygen quantum yield ΦΔ of 99% and is water sol. and photostable. Moreover, it contains a pos. charge for good adherence to cell walls of pathogens. In this study, the PIB properties of SAPYR were investigated against monospecies and polyspecies biofilms formed in vitro by oral key pathogens. SAPYR showed a dual mechanism of action against biofilms: (I) it disrupts the structure of the biofilm even without illumination; (II) when irradiated, it inactivates bacteria in a polymicrobial biofilm after one single treatment with an efficacy of ≥99.99%. These results encourage further investigation on the potential of PIB using SAPYR for the treatment of localized infectious diseases.59Späth, A.; Leibl, C.; Cieplik, F.; Lehner, K.; Regensburger, J.; Hiller, K. A.; Bäumler, W.; Schmalz, G.; Maisch, T. Improving Photodynamic Inactivation of Bacteria in Dentistry: Highly Effective and Fast Killing of Oral Key Pathogens With Novel Tooth-Colored Type-II Photosensitizers. J. Med. Chem. 2014, 57, 5157– 5168, DOI: 10.1021/jm4019492[ACS Full Text], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cjnvVSjsg%253D%253D&md5=893d2358da7841c845529cf4af43d4c7Improving photodynamic inactivation of bacteria in dentistry: highly effective and fast killing of oral key pathogens with novel tooth-colored type-II photosensitizersSpath Andreas; Leibl Christoph; Cieplik Fabian; Lehner Karin; Regensburger Johannes; Hiller Karl-Anton; Baumler Wolfgang; Schmalz Gottfried; Maisch TimJournal of medicinal chemistry (2014), 57 (12), 5157-68 ISSN:.Increasing antibiotic resistances in microorganisms create serious problems in public health. This demands alternative approaches for killing pathogens to supplement standard treatment methods. Photodynamic inactivation of bacteria (PIB) uses light activated photosensitizers (PS) to generate reactive oxygen species immediately upon illumination, inducing lethal phototoxicity. Positively charged phenalen-1-one derivatives are a new generation of PS for light-mediated killing of pathogens with outstanding singlet oxygen quantum yield ΦΔ of >97%. Upon irradiation with a standard photopolymerizer light (bluephase C8, 1260 ± 50 mW/cm(2)) the PS showed high activity against the oral key pathogens Enterococcus faecalis, Actinomyces naeslundii, Streptococcus mutans, and Aggregatibacter actinomycetemcomitans. At a concentration of 10 μM, a maximum efficacy of more than 6 log10 steps (≥ 99.9999%) of bacteria killing is reached in less than 1 min (light dose 50 J/cm(2)) after one single treatment. The pyridinium substituent as positively charged moiety is especially advantageous for antimicrobial action.60Gill, M. R.; Thomas, J. A. Ruthenium(II) Polypyridyl Complexes and DNA - From Structural Probes to Cellular Imaging and Therapeutics. Chem. Soc. Rev. 2012, 41, 3179– 3192, DOI: 10.1039/c2cs15299a[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XksVOhtbY%253D&md5=0e99085c63eadb273a7532616e85b8d2Ruthenium(II) polypyridyl complexes and DNA-from structural probes to cellular imaging and therapeuticsGill, Martin R.; Thomas, Jim A.Chemical Society Reviews (2012), 41 (8), 3179-3192CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. In the last few decades, coordination complexes based on d6 metal centers and polypyridyl ligand architectures been developed as structure- and site-specific reversible DNA binding agents. Due to their attractive photophys. properties, much of this research has focused on complexes based on ruthenium(II) centers and, more recently, attention has turned to the use of these complexes in biol. contexts. As the rules that govern the cellular uptake and cellular localization of such systems are detd. they are finding numerous applications ranging from imaging to therapeutics. This review illustrates how the interdisciplinary nature of this research-which takes in synthetic chem., biophys. and in cellulo studies-makes this an exciting area in which an array of further applications are likely to emerge.61Fong, J.; Kasimova, K.; Arenas, Y.; Kaspler, P.; Lazic, S.; Mandel, A.; Lilge, L. A Novel Class of Ruthenium-Based Photosensitizers Effectively Kills In Vitro Cancer Cells and In Vivo Tumors. Photochem. Photobiol. Sci. 2015, 14, 2014– 2023, DOI: 10.1039/C4PP00438H[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitlyitL8%253D&md5=39f2dd8af513b916a677aa7c9fd009e2A novel class of ruthenium-based photosensitizers effectively kills in vitro cancer cells and in vivo tumorsFong, Jamie; Kasimova, Kamola; Arenas, Yaxal; Kaspler, Pavel; Lazic, Savo; Mandel, Arkady; Lilge, LotharPhotochemical & Photobiological Sciences (2015), 14 (11), 2014-2023CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)The photo-phys. and photo-biol. properties of two small (<2 kDa), novel Ru(II) photosensitizers (PSs) referred to as TLD1411 and TLD1433 are presented. Both PSs are highly water-sol., provide only very limited luminescence emission at 580-680 nm following excitation at 530 nm, and demonstrate high photostability with less than 50% photobleaching at radiant exposures H = 275 J cm-2 (530 nm irradn.). It was previously shown that these two photosensitizers exhibit a large singlet oxygen (1O2) quantum yield (Φ (Δ) ∼0.99 in acetonitrile). Their photon-mediated efficacy to cause cell death (λ = 530 nm, H = 45 J cm-2) was tested in vitro in colon and glioma cancer cell lines (CT26.WT, CT26.CL25, F98, and U87) and demonstrated a strong photodynamic effect with complete cell death at concns. as low as 4 and 1 μM for TLD1411 and TLD1433, resp. Notably, dark toxicity was negligible at concns. less than 25 and 10 μM for TLD1411 and TLD1433, resp. The ability of the PSs to initiate Type I photoreactions was tested by exposing PS-treated U87 cells to light under hypoxic conditions (pO2 < 0.5%), which resulted in a complete loss of the PDT effect. In vivo, the max. tolerated doses 50 (MTD50) were detd. to be 36 mg kg-1 (TLD1411) and 103 mg kg-1 (TLD1433) using the BALB/c murine model. In vivo growth delay studies in the s.c. colon adenocarcinoma CT26. WT murine model were conducted at a photosensitizer dose equal to 0.5 and 0.2 MTD50 for TLD1411 and TLD1433, resp. 4 h post PS injection, tumors were irradiated with continuous wave or pulsed light sources (λ = 525-530 nm, H = 192 J cm-2). Overall, treatment with continuous wave light demonstrated a higher tumor destruction efficacy when compared to pulsed light. TLD1433 mediated PDT resulted in statistically significant longer animal survival compared to TLD1411. Two-thirds of TLD1433-treated mice survived more than 100 days (p < 0.01) whereas TLD1411-treated mice did not survive longer than 20 days. Here we present evidence that two novel PSs have very potent photo-biol. properties and are able to cause PDT-mediated cell death in both in vitro cell culture models and in vivo tumor regression.62Angeles-Boza, A. M.; Bradley, P. M.; Fu, P. K. L.; Wicke, S. E.; Bacsa, J.; Dunbar, K. R.; Turro, C. Dna Binding and Photocleavage in Vitro by New Dirhodium(II) Dppz Complexes: Correlation to Cytotoxicity and Photocytotoxicity. Inorg. Chem. 2004, 43, 8510– 8519, DOI: 10.1021/ic049091h[ACS Full Text], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpvVGgs70%253D&md5=1d4647671e01eccb4466c37889b9534eDNA Binding and Photocleavage in Vitro by New Dirhodium(II) dppz Complexes: Correlation to Cytotoxicity and PhotocytotoxicityAngeles-Boza, Alfredo M.; Bradley, Patricia M.; Fu, Patty K.-L.; Wicke, Sara E.; Bacsa, John; Dunbar, Kim R.; Turro, ClaudiaInorganic Chemistry (2004), 43 (26), 8510-8519CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)Two new dirhodium(II) complexes possessing the intercalating dppz ligand (dppz = dipyrido[3,2-a:2',3'-c]phenazine), cis-[Rh2(μ-O2CCH3)2(dppz)(η1-O2CCH3)(CH3OH)]+ (1) and cis-[Rh2(μ-O2CCH3)2(dppz)2]2+ (2), were synthesized and characterized as potential agents for photochemotherapy. Various techniques show that 1 binds to DNA through intercalation, although some aggregation of the complex on the DNA surface is also present. In contrast, 2 does not intercalate between the DNA bases; however, strong hypochromic behavior is obsd. in the presence of DNA, which can be attributed to intermol. π-stacking of 2 enhanced by the polyanion. The apparent DNA binding consts. detd. using optical titrns. are compared to those from dialysis expts. Both complexes photocleave pUC18 plasmid in vitro under irradn. with visible light (λirr ≥ 395 nm, 15 min), resulting in the nicked, circular form. Greater photocleavage is obsd. for 1 relative to 2, which may be due to the ability of 1 to intercalate between the DNA bases. The cytotoxicity toward human skin cells (Hs-27) measured as the concn. at which 50% cell death is recorded, LC50, was found to be 135±8 μM for 2 in the dark (30 min), which is significantly lower than those of 1 (LC50 = 27±2 μM) and Rh2(O2CCH3)4 (LC50 = 15±2 μM). Irradn. of cell cultures contg. 1 and Rh2(O2CCH3)4 with visible light (400-700 nm, 30 min) has little effect on their cytotoxicity, with LC50 values of 21±3 and 13±2 μM, resp. Interestingly, a 3.4-fold increase in the toxicity of 2 is obsd. when the cell cultures are irradiated (400-700 nm, 30 min), resulting in LC50 = 39±1 μM. The greater toxicity of 1 compared to 2 in the dark may be related to the ability of the former compd. to intercalate between the DNA bases. The lower cytotoxicity of 2, together with its significantly greater photocytotoxicity, makes this complex a potential agent for photodynamic therapy (PDT). These results suggest that intercalation or strong DNA binding may not be a desirable property of a potential PDT agent.63Li, Y.; Tan, C.-P.; Zhang, W.; He, L.; Ji, L.-N.; Mao, Z.-W. Phosphorescent Iridium(III)-Bis-N-Heterocyclic Carbene Complexes as Mitochondria-Targeted Theranostic and Photodynamic Anticancer Agents. Biomaterials 2015, 39, 95– 104, DOI: 10.1016/j.biomaterials.2014.10.070[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVyhsrjM&md5=cd8df6801aa88858a2a63a39d6727384Phosphorescent iridium(III)-bis-N-heterocyclic carbene complexes as mitochondria-targeted theranostic and photodynamic anticancer agentsLi, Yi; Tan, Cai-Ping; Zhang, Wei; He, Liang; Ji, Liang-Nian; Mao, Zong-WanBiomaterials (2015), 39 (), 95-104CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Mitochondria-targeted compds. represent a promising approach to target tumors selectively and overcome resistance to current anticancer therapies. In this work, 3 cyclometalated iridium(III) complexes (1-3) contg. bis-N-heterocyclic carbene (NHC) ligands were explored as theranostic and photodynamic agents targeting mitochondria. These complexes display rich photophys. properties, which greatly facilitates the study of their intracellular fate. All 3 complexes are more cytotoxic than cisplatin against the cancer cells screened. 1-3 can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, and they can carry out theranostic functions by simultaneously inducing and monitoring the morphol. changes in mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy by initiating a cascade of events related to mitochondrial dysfunction. Addnl., they display up to 3 orders of magnitude higher cytotoxicity upon irradn. at 365 nm, which is so far the highest photocytotoxic responses reported for iridium complexes.64To, W. P.; Zou, T.; Sun, R. W. Y.; Che, C. M. Light-Induced Catalytic and Cytotoxic Properties of Phosphorescent Transition Metal Compounds with a D8 Electronic Configuration. Philos. Trans. R. Soc., A 2013, 371, 20120126, DOI: 10.1098/rsta.2012.0126[Crossref], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1yhtbvM&md5=e624be429c6231d604ddeac30715e0ccLight-induced catalytic and cytotoxic properties of phosphorescent transition metal compounds with a d8 electronic configurationTo, Wai-Pong; Zou, Taotao; Sun, Raymond Wai-Yin; Che, Chi-MingPhilosophical Transactions of the Royal Society, A: Mathematical, Physical & Engineering Sciences (2013), 371 (1995), 20120126/1-20120126/19CODEN: PTRMAD; ISSN:1364-503X. (Royal Society)Transition metal compds. are well documented to have diverse applications such as in catalysis, light-emitting materials and therapeutics. In the areas of photocatalysis and photodynamic therapy, metal compds. of heavy transition metals are highly sought after because they can give rise to triplet excited states upon photoexcitation. The long lifetimes (more than 1 μs) of the triplet states of transition metal compds. allow for bimol. reactions/processes such as energy transfer and/or electron transfer to occur. Reactions of triplet excited states of luminescent metal compds. with oxygen in cells may generate reactive oxygen species and/or induce damage to DNA, leading to cell death. This article recaps the recent findings on photochem. and phototoxic properties of luminescent platinum(II) and gold(III) compds. both from the literature and exptl. results from our group.65Senge, M. O. MTHPC - A Drug on Its Way from Second to Third Generation Photosensitizer? Photodiagnosis Photodyn. Photodiagn. Photodyn. 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The BF2-chelated tetraaryl-azadipyrromethenes (ADPMs) are an emerging class of non-porphyrin PDT agent, which have previously shown excellent photochem. and photophys. properties for therapeutic application. Herein, in vivo efficacy and mechanism of action studies have been completed for the lead agent, ADMP06. A multi-modality imaging approach was employed to assess efficacy of treatment, as well as probe the mechanism of action of ADPM06-mediated PDT. Tumor ablation in 71% of animals bearing mammary tumors was achieved after delivery of 2 mg/kg-1 of ADPM06 followed immediately by light irradn. with 150 J/cm-2. The inherent fluorescence of ADPM06 was utilized to monitor organ biodistribution patterns, with fluorescence reaching baseline levels in all organs within 24 h. 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Sturua Lela; Sunguya Bruno F; Swaminathan Soumya; Swaroop Mamta; Sykes Bryan L; Tabb Karen M; Takahashi Ken; Talongwa Roberto T; Tandon Nikhil; Tanne David; Tanner Marcel; Tavakkoli Mohammad; Te Ao Braden J; Teixeira Carolina M; Tellez Rojo Martha M; Terkawi Abdullah S; Texcalac-Sangrador Jose Luis; Thackway Sarah V; Thomson Blake; Thorne-Lyman Andrew L; Thrift Amanda G; Thurston George D; Tillmann Taavi; Tobollik Myriam; Tonelli Marcello; Topouzis Fotis; Towbin Jeffrey A; Toyoshima Hideaki; Traebert Jefferson; Tran Bach X; Trasande Leonardo; Trillini Matias; Trujillo Ulises; Dimbuene Zacharie Tsala; Tsilimbaris Miltiadis; Tuzcu Emin Murat; Uchendu Uche S; Ukwaja Kingsley N; Uzun Selen B; van de Vijver Steven; Van Dingenen Rita; van Gool Coen H; van Os Jim; Varakin Yuri Y; Vasankari Tommi J; Vasconcelos Ana Maria N; Vavilala Monica S; Veerman Lennert J; Velasquez-Melendez Gustavo; Venketasubramanian N; Vijayakumar Lakshmi; Villalpando Salvador; Violante Francesco S; Vlassov Vasiliy Victorovich; Vollset Stein Emil; Wagner Gregory R; Waller Stephen G; Wallin Mitchell T; Wan Xia; Wang Haidong; Wang JianLi; Wang Linhong; Wang Wenzhi; Wang Yanping; Warouw Tati S; Watts Charlotte H; Weichenthal Scott; Weiderpass Elisabete; Weintraub Robert G; Werdecker Andrea; Wessells K Ryan; Westerman Ronny; Whiteford Harvey A; Wilkinson James D; Williams Hywel C; Williams Thomas N; Woldeyohannes Solomon M; Wolfe Charles D A; Wong John Q; Woolf Anthony D; Wright Jonathan L; Wurtz Brittany; Xu Gelin; Yan Lijing L; Yang Gonghuan; Yano Yuichiro; Ye Pengpeng; Yenesew Muluken; Yentur Gokalp K; Yip Paul; Yonemoto Naohiro; Yoon Seok-Jun; Younis Mustafa Z; Younoussi Zourkaleini; Yu Chuanhua; Zaki Maysaa E; Zhao Yong; Zheng Yingfeng; Zhou Maigeng; Zhu Jun; Zhu Shankuan; Zou Xiaonong; Zunt Joseph R; Lopez Alan D; Vos Theo; Murray Christopher JLancet (London, England) (2015), 386 (10010), 2287-323 ISSN:.BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. FINDINGS: All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8-58·5) of deaths and 41·6% (40·1-43·0) of DALYs. Risks quantified account for 87·9% (86·5-89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks. FUNDING: Bill & Melinda Gates Foundation.73Baskaran, R.; Lee, J.; Yang, S.-G. Clinical Development of Photodynamic Agents and Therapeutic Applications. Biomater. Res. 2018, 22, 1, DOI: 10.1186/s40824-018-0140-z74Lovell, J. F.; Liu, T. W. B.; Chen, J.; Zheng, G. Activatable Photosensitizers for Imaging and Therapy. Chem. Rev. 2010, 110, 2839– 2857, DOI: 10.1021/cr900236h[ACS Full Text], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1Sgu7k%253D&md5=c6bd3c7a45733ed230b04715a9477d39Activatable Photosensitizers for Imaging and TherapyLovell, Jonathan F.; Liu, Tracy W. B.; Chen, Juan; Zheng, GangChemical Reviews (Washington, DC, United States) (2010), 110 (5), 2839-2857CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review.75Derycke, A. S. L.; De Witte, P. A. M. Liposomes for Photodynamic Therapy. Adv. Drug Delivery Rev. 2004, 56, 17– 30, DOI: 10.1016/j.addr.2003.07.014[Crossref], [PubMed], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXos1Oh&md5=56dc813022f44d3fb6977962f87633e6Liposomes for photodynamic therapyDerycke, Annelies S. L.; de Witte, Peter A. M.Advanced Drug Delivery Reviews (2004), 56 (1), 17-30CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science B.V.)A review. Photodynamic therapy (PDT) is an evolving modality for the treatment of superficial tumors. The technique utilizes photosensitizing agents that are able to photochem. eradicate malignant cells. With the aim of improving the tumoritropic behavior of photosensitizers, liposomes are presently being used as carrier and delivery systems for PDT. This review covers the different liposomal strategies that are available to target photosensitizers to tumor tissue. In general, conventional liposomes carrying photosensitizers are not able to establish elevated tumor-to-normal tissue ratios, hampering their generalized use as tumoritropic carriers of photosensitizers. Conversely, liposomes with a specifically modified design, i.e. long-circulating and esp. actively targeting liposomes, stand a better chance in becoming truly tumoritropic carriers of photosensitizers. Strategies that can be employed to trigger the release of photosensitizer mols. from the liposomes are also discussed. The examd. topics are supplemented with examples of the latest developments in the field of photodynamic therapy.76Postigo, F.; Mora, M.; De Madariaga, M. A.; Nonell, S.; Sagristá, M. L. Incorporation of Hydrophobic Porphyrins Into Liposomes: Characterization and Structural Requirements. Int. J. Pharm. 2004, 278, 239– 254, DOI: 10.1016/j.ijpharm.2004.03.004[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXkslKmu7w%253D&md5=a7310c64f7a2832a3b8934e469c558bcIncorporation of hydrophobic porphyrins into liposomes: characterization and structural requirementsPostigo, F.; Mora, M.; De Madariaga, M. A.; Nonell, S.; Sagrista, M. L.International Journal of Pharmaceutics (2004), 278 (2), 239-254CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)The ability of photosensitizers to give reactive oxygenated products is considered decisive for photodynamic applications, but the hydrophobic nature of many porphyrins makes necessary to obtain suitable pharmaceutical formulations. This paper reports the structural photosensitizer features that allow the prepn. of stable liposomal formulations. Metalated and non-metalated TPPs (tetraphenylporphines) and TPyPs (tetrapyridylporphines) and different lipid/porphyrin ratios were considered in order to procure liposomal prepns. contg. porphyrin concns. adequate to necessary doses. The results show that the incorporation of porphyrins into liposomes can be related with their ability to form aggregates in a watery media. Thus, ZnTPP, which structural properties avoid the formation of aggregates, was efficiently incorporated into stable liposomes. Moreover, the efficient generation of singlet oxygen by ZnTPP liposomal suspensions has been shown. Because of this, the synthesis of hydrophobic porphyrin derived structures or other sensitizers, which do not aggregate in a watery media and with Q-bands shifted to higher λ values than ZnTPP, will be efficiently incorporated into liposomes and useful for clin. applications.77Park, W.; Park, S.-J.; Cho, S.; Shin, H.; Jung, Y.-S.; Lee, B.; Na, K.; Kim, D.-H. Intermolecular Structural Change for Thermoswitchable Polymeric Photosensitizer. J. Am. Chem. Soc. 2016, 138, 10734– 10737, DOI: 10.1021/jacs.6b04875[ACS Full Text], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlOgtrvK&md5=dec8732903f907918d0ed2a2d8f5d429Intermolecular Structural Change for Thermoswitchable Polymeric PhotosensitizerPark, Wooram; Park, Sin-Jung; Cho, Soojeong; Shin, Heejun; Jung, Young-Seok; Lee, Byeongdu; Na, Kun; Kim, Dong-HyunJournal of the American Chemical Society (2016), 138 (34), 10734-10737CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)We developed a thermoswitchable polymeric photosensitizer (T-PPS) by conjugating PS (Pheophorbide-a, PPb-a) to a temp.-responsive polymer backbone of biocompatible hydroxypropyl cellulose. Self-quenched PS mols. linked in close proximity by π-π stacking in T-PPS were easily transited to an active monomeric state by the temp.-induced phase transition of polymer backbones. The temp.-responsive intermol. interaction changes of PS mols. in T-PPS were demonstrated in synchrotron small-angle X-ray scattering and UV-vis spectrophotometer anal. The T-PPS allowed switchable activation and synergistically enhanced cancer cell killing effect at the hyperthermia temp. (45 °C). Our developed T-PPS has the considerable potential not only as a new class of photomedicine in clinics but also as a biosensor based on temp. responsiveness.78Lee, C. S.; Na, K. Photochemically Triggered Cytosolic Drug Delivery Using PH-Responsive Hyaluronic Acid Nanoparticles for Light-Induced Cancer Therapy. Biomacromolecules 2014, 15, 4228– 4238, DOI: 10.1021/bm501258s[ACS Full Text], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1Sju7fE&md5=60fa6709baca8b057d37ba9ad9083b93Photochemically Triggered Cytosolic Drug Delivery Using pH-Responsive Hyaluronic Acid Nanoparticles for Light-Induced Cancer TherapyLee, Chung-Sung; Na, KunBiomacromolecules (2014), 15 (11), 4228-4238CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)A photochem. triggered cytosolic drug delivery system based on combining tumor-targeting pH-responsive hyaluronic acid (HA) nanoparticles (PHANs) with anticancer therapeutics (doxorubicin; DOX) was successfully developed for light-induced cancer therapy. PHANs were prepd. through the self-assembly of a photosensitizer (PS), chlorin e6, and a pH-responsive moiety, poly(diisopropylaminoethyl) aspartamide (PDIPASP),conjugated to HA. DOX encapsulating PHANs ([email protected]) have a uniform spherical shape,a sub-100 nm size distribution and a neg. surface charge. The pH-responsiveness of PHANs leads to their disassembly due to the protonation of PDIPASP, which triggers DOX release. Competitive cellular uptake and confocal microscopy studies revealed CD44 receptor-mediated endocytosis, endosomal escape capability and efficient drug targeting. Compared to treatment with free DOX or PHANs, the combined treatment with [email protected] and spatiotemporally defined irradn. remarkably improved the anticancer efficacy both in vitro and in vivo studies. Therefore, this strategy shows promise for the photochem. triggered cytosolic drug delivery of therapeutic agents for light-induced cancer therapy.79Kim, K.; Lee, C. S.; Na, K. Light-Controlled Reactive Oxygen Species (ROS)-Producible Polymeric Micelles with Simultaneous Drug-Release Triggering and Endo/Lysosomal Escape. Chem. Commun. 2016, 52, 2839– 2842, DOI: 10.1039/C5CC09239F[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xlt1Klug%253D%253D&md5=a4bd7e31062ed97bd9dd3b9c1bc4ae8bLight-controlled reactive oxygen species (ROS)-producible polymeric micelles with simultaneous drug-release triggering and endo/lysosomal escapeKim, Kihong; Lee, Chung-Sung; Na, KunChemical Communications (Cambridge, United Kingdom) (2016), 52 (13), 2839-2842CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A doxorubicin (DOX)-loaded and light-induced ROS-producing polymeric micelle (D-LRPM), in which light triggers simultaneous DOX-release and endo/lysosomal escape, produces a powerful, spatiotemporally controllable, therapeutic efficacy for tumor treatment.80Park, S.; Park, W.; Na, K. Tumor Intracellular-Environment Responsive Materials Shielded Nano-Complexes for Highly Efficient Light-Triggered Gene Delivery without Cargo Gene Damage. Adv. Funct. Mater. 2015, 25, 3472– 3482, DOI: 10.1002/adfm.201500737[Crossref], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnvV2qurY%253D&md5=70af0df6f4b2943bb34306f25be89918Tumor intracellular-environment responsive materials shielded nano-complexes for highly efficient light-triggered gene delivery without Cargo Gene DamagePark, Sin-jung; Park, Wooram; Na, KunAdvanced Functional Materials (2015), 25 (23), 3472-3482CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)Gene therapy has great potential to bring tremendous improvement to cancer therapy. Recently, photochem. internalization (PCI) has provided the opportunity to overcome endo-lysosomal sequestration, which is one of the main bottlenecks in both gene and chemotherapeutic delivery. Despite PCI having shown great potential in gene delivery systems, it still remains difficult to perform due to the photo-oxidn. of exogenous cargo genes by reactive oxygen species (ROS) generated from activated photosensitizers (PSs). In this paper, a new type of a stable light-triggered gene delivery system is demonstrated based on endo-lysosomal pH-responsive polymeric PSs, which serve as shielding material for the polymer/gene complex. By taking advantage of the endo-lysosomal pH-sensitive de-shielding ability of the pH-responsive shielding material incorporated in the ternary gene complexes (pH-TCs), a more significant photo-triggered gene expression effect is achieved without damage to the gene from ROS. In contrast, pH-insensitive material-shielded nanocarriers cause photo-oxidn. of the payload and do not generate a notable transfection efficacy. Importantly, with the benefit of our newly developed gene delivery system, the deep penetration issue can be resolved. Finally, the light-triggered gene delivery system using pH-TCs is applied to deliver the therapeutic p53 gene in melanoma K-1735 bearing mice, showing excellent therapeutic potential for cancer.81Jo, Y.-u.; Lee, C. B.; Bae, S. K.; Na, K. Acetylated Hyaluronic Acid-Poly(L-Lactic Acid) Conjugate Nanoparticles for Inhibition of Doxorubicinol Production from Doxorubicin. Macromol. Res. 2020, 28, 67– 73, DOI: 10.1007/s13233-020-8003-6[Crossref], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsF2rt7%252FI&md5=90c11f5c8bb2bc47fed47b57f8db736fAcetylated hyaluronic acid-poly(L-lactic acid) conjugate nanoparticles for inhibition of doxorubicinol production from doxorubicinJo, Young-um; Lee, Chae Bin; Bae, Soo Kyung; Na, KunMacromolecular Research (2020), 28 (1), 67-73CODEN: MRAECT; ISSN:1598-5032. (Polymer Society of Korea)In this study, doxorubicin (DOX)-induced cardiotoxicity was overcome using cancer-recognizable DOX-loaded acetylated hyaluronic aicd-poly(L-lactic acid) (AcHA-PLLA) nanoparticles (DHPs). AcHA-PLLA was synthesized via ring opening polymn. of L-lactide with AcHA as a macroinitiator and characterized by 1H NMR and crit. micelle concn. DHPs were formed by self-assembly via dialysis, were estd. to be 160.7 ± 2.7 nm in av. diam., exhibited a slow rate release profile, and prevented DOX from being degraded in the circulation. In addn., DHPs demonstrated efficient cellular uptake into a colorectal cancer cell line (HCT-116) by CD44 receptor-mediated endocytosis, which was confirmed by in vitro cellular uptake, the competitive inhibition assay with free HA and flow cytometry. Furthermore, DHPs exhibited therapeutic efficacy against HCT-116 cells through receptor-mediated endocytosis: DHPs with free hyaluronic acid (HA) demonstrated 2-fold higher cell viability than DHPs without free HA. DHPs also inhibited doxorubicinol prodn., which induces cardiotoxicity, from DOX in vivo. The area-under-the-curve (AUC) of DOX administered as free DOX was 109.0 ± 25.0 μg min mL-1 and that from DHPs was 97.2 ± 10.2 μg min mL-1. Although these are comparable, the AUC of doxorubicinol was 1.36 ± 0.18 μg min mL-1 and 0.45 ± 0.12 μg min mL-1, with the treatment of free DOX-HCl and DHPs, resp., demonstrating the redn. of the metabolic conversion of DOX to doxorubicinol in plasma. These results indicate the role of DHPs in preventing DOX transformation into doxorubicinol, which may contribute to the reduced toxicity. DHPs are promising cancer therapeutic nanoparticles, because they are highly biocompatible and tumor-recognizable, and prevent the DOX transformation.. [Figure not available: see fulltext.].82Kim, J.; Kim, K. S.; Park, S. J.; Na, K. Vitamin Bc-Bearing Hydrophilic Photosensitizer Conjugate for Photodynamic Cancer Theranostics. Macromol. Biosci. 2015, 15, 1081– 1090, DOI: 10.1002/mabi.201500060[Crossref], [PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlsVyis7s%253D&md5=ecebda7f21c4e7e21b2088f56737a1faVitamin Bc-bearing hydrophilic photosensitizer conjugate for photodynamic cancer theranosticsKim, Jiyoung; Kim, Kyoung Sub; Park, Sin-jung; Na, KunMacromolecular Bioscience (2015), 15 (8), 1081-1090CODEN: MBAIBU; ISSN:1616-5187. (Wiley-VCH Verlag GmbH & Co. KGaA)The accurate diagnosis and proper therapy for cancer are essential to improve the success rate of cancer treatment. Here, we demonstrated that the vitamin Bc-bearing hydrophilic photosensitizer conjugate folic acid-polyethylene glycol-pheophorbideA (FA-PEG-PheoA) has been synthesized for the intracellular diagnosis and photodynamic therapy of a tumor. The synthesized vitamin Bc-bearing hydrophilic photosensitizer conjugate has been characterized for the folic acid receptor expressing the ability to target tumor cells, which is facilitated by the chem. conjugation with folic acid. The vitamin Bc-bearing hydrophilic photosensitizer conjugate internalization mechanism was identified through a competitive inhibition test with free folic acid. We optimized the laser-sensitive, cytotoxicity changeable, vitamin Bc-bearing hydrophilic photosensitizer conjugate concn., which is non-cytotoxic under normal conditions and specifically cytotoxic toward cancer cells (max. 69.15%) under laser irradn. conditions used for theranostic agents. The cancer therapeutic and diagnosis effects of synthesized conjugate were confirmed in MDA-MB-231 cells and MDA-MB-231-bearing mice. As a result, the vitamin Bc-bearing hydrophilic photosensitizer conjugate exhibited a highly photodynamic therapeutic effect, which enabled the selective detection of a folic acid receptor expressing cancer using optical imaging.83Temizel, E.; Sagir, T.; Ayan, E.; Isik, S.; Ozturk, R. Delivery of Lipophilic Porphyrin by Liposome Vehicles: Preparation and Photodynamic Therapy Activity Against Cancer Cell Lines. Photodiagn. Photodyn. Ther. 2014, 11, 537– 545, DOI: 10.1016/j.pdpdt.2014.07.006[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlCis77N&md5=f7cca13fee49c59c9ec19f71c029a192Delivery of lipophilic porphyrin by liposome vehicles: Preparation and photodynamic therapy activity against cancer cell linesTemizel, Emine; Sagir, Tugba; Ayan, Esra; Isik, Sevim; Ozturk, RamazanPhotodiagnosis and Photodynamic Therapy (2014), 11 (4), 537-545CODEN: PPTHBF; ISSN:1572-1000. (Elsevier B.V.)Porphyrin photosensitizers are mostly used components in photodynamic therapy (PDT). The poor soly. of porphyrins in aq. medium is the problem to be solved for the in vivo applications. The delivery of photosensitizers to the tumor cells using liposome vehicles can help to overcome this problem. In this work, we have first functionalized the protoporphyrin IX with lipophilic oleylamine arms and encapsulated it into 1,2 dioleyl-sn-glycero-phosphatidylcholine (DOPC) liposomes. The appropriate sizes of liposomes are about 140 nm and have the characteristic Soret and Q band absorptions at 405 nm (Soret), 507 nm, 541 nm, 577 nm and 631 nm (Q bands), resp. In the photodynamic activity studies, the liposomal porphyrins were irradiated with light (375 nm, 10 mW) in the presence of cancer cell lines, HeLa and AGS. We have found that both liposomal porphyrins and oleylamine conjugated porphyrins are much more effective than PpIX. This result can be attributed to the drug delivery characteristic of the liposomes which plays effective role in endocytosis. We also found that, in AGS cells, liposomal PpIX-Ole induced apoptosis more than HeLa cells under light conditions.84Master, A.; Livingston, M.; Sen Gupta, A. Photodynamic Nanomedicine in the Treatment of Solid Tumors: Perspectives and Challenges. J. Controlled Release 2013, 168, 88– 102, DOI: 10.1016/j.jconrel.2013.02.020[Crossref], [PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXotF2gsrs%253D&md5=2e0bea8eebd6f9c739d5cc469bf638e1Photodynamic nanomedicine in the treatment of solid tumors: Perspectives and challengesMaster, Alyssa; Livingston, Megan; Sen Gupta, AnirbanJournal of Controlled Release (2013), 168 (1), 88-102CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A review. Photodynamic therapy (PDT) is a promising treatment strategy where activation of photosensitizer drugs with specific wavelengths of light results in energy transfer cascades that ultimately yield cytotoxic reactive oxygen species which can render apoptotic and necrotic cell death. Without light the photosensitizer drugs are minimally toxic and the photoactivating light itself is non-ionizing. Therefore, harnessing this mechanism in tumors provides a safe and novel way to selectively eradicate tumor with reduced systemic toxicity and side effects on healthy tissues. For successful PDT of solid tumors, it is necessary to ensure tumor-selective delivery of the photosensitizers, as well as, the photoactivating light and to establish dosimetric correlation of light and drug parameters to PDT-induced tumor response. To this end, the nanomedicine approach provides a promising way towards enhanced control of photosensitizer biodistribution and tumor-selective delivery. In addn., refinement of nanoparticle designs can also allow incorporation of imaging agents, light delivery components and dosimetric components. This review aims at describing the current state-of-the-art regarding nanomedicine strategies in PDT, with a comprehensive narrative of the research that has been carried out in vitro and in vivo, with a discussion of the nanoformulation design aspects and a perspective on the promise and challenges of PDT regarding successful translation into clin. application.85Ogawara, K. I.; Higaki, K. Nanoparticle-Based Photodynamic Therapy: Current Status and Future Application to Improve Outcomes of Cancer Treatment. Chem. Pharm. Bull. 2017, 65, 637– 641, DOI: 10.1248/cpb.c17-00063[Crossref], [PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXis1Cltbc%253D&md5=425994e84dd63ba6bc0f9012b7b89cc0Nanoparticle-based photodynamic therapy: current status and future application to improve outcomes of cancer treatmentOgawara, Ken-ichi; Higaki, KazutakaChemical & Pharmaceutical Bulletin (2017), 65 (7), 637-641CODEN: CPBTAL; ISSN:0009-2363. (Pharmaceutical Society of Japan)A review. Photodynamic therapy (PDT) is an emerging cancer treatment that uses photosensitizers (PS), along with light to activate them, resulting in oxidn. of various biol. components in cancer tissues. However, since most potential PS are solubilized and given as aq. soln., PS is non-specifically distributed in the body, leading to the induction of various side effects in normal tissues that are exposed to daylight such as skin and eyes. To overcome the problem assocd. with non-specific in vivo disposition of PS, various approaches have been applied to develop safer dosage forms for PS with more efficient tumor delivery and lower disposition to normal tissues. Passive drug targeting to tumors with nanoparticulate formulations has been recognized as one of the potentially useful approaches to improve the poor tissue specificity of conventional cancer chemotherapy and this approach should also be applicable for more efficient tumor delivery of PS. In this review article, several issues concerning the efficacy of PDT using nanoparticle-based formulations are discussed and our recent attempts to temporally enhance the vascular permeability within tumors with photodynamic treatment for the better therapeutic outcome of nanoparticle-based therapy are introduced.86Tada, D. B.; Baptista, M. S. Photosensitizing Nanoparticles and the Modulation of ROS Generation. Front. Chem. 2015, 3, 33, DOI: 10.3389/fchem.2015.00033[Crossref], [PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mbjs1Kqsw%253D%253D&md5=b23f1943112836d0068f0d7bead9bd6cPhotosensitizing nanoparticles and the modulation of ROS generationTada Dayane B; Baptista Mauricio SFrontiers in chemistry (2015), 3 (), 33 ISSN:2296-2646.The association of PhotoSensitizer (PS) molecules with nanoparticles (NPs) forming photosensitizing NPs, has emerged as a therapeutic strategy to improve PS tumor targeting, to protect PS from deactivation reactions and to enhance both PS solubility and circulation time. Since association with NPs usually alters PS photophysical and photochemical properties, photosensitizing NPs are an important tool to modulate ROS generation. Depending on the design of the photosensitizing NP, i.e., type of PS, the NP material and the method applied for the construction of the photosensitizing NP, the deactivation routes of the excited state can be controlled, allowing the generation of either singlet oxygen or other reactive oxygen species (ROS). Controlling the type of generated ROS is desirable not only in biomedical applications, as in Photodynamic Therapy where the type of ROS affects therapeutic efficiency, but also in other technological relevant fields like energy conversion, where the electron and energy transfer processes are necessary to increase the efficiency of photoconversion cells. The current review highlights some of the recent developments in the design of Photosensitizing NPs aimed at modulating the primary photochemical events after light absorption.87Konan, Y. N.; Gurny, R.; Allémann, E. State of the Art in the Delivery of Photosensitizers for Photodynamic Therapy. J. Photochem. Photobiol., B 2002, 66, 89– 106, DOI: 10.1016/S1011-1344(01)00267-6[Crossref], [PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhvVChtL8%253D&md5=85e0a2b90a07196b695ee4a024847857State of the art in the delivery of photosensitizers for photodynamic therapyKonan, Yvette Niamien; Gurny, Robert; Allemann, EricJournal of Photochemistry and Photobiology, B: Biology (2002), 66 (2), 89-106CODEN: JPPBEG; ISSN:1011-1344. (Elsevier Science B.V.)A review. In photodynamic therapy, one of the problems limiting the use of many photosensitizers (PS) is the difficulty in prepg. pharmaceutical formulations that enable their parenteral administration. Due to their low water soly., the hydrophobic PS cannot be simply injected i.v. Different strategies, including polymer-PS conjugation or encapsulation of the drug in colloidal carriers such as oil-dispersions, liposomes and polymeric particles, have been investigated. Although these colloidal carriers tend to accumulate selectively in tumor tissues, they are rapidly taken up by the mononuclear phagocytic system. In order to reduce this undesirable uptake by phagocytic cells, long-circulating carriers that consist of surface modified carriers have been developed. Moreover, considerable effort has been directed towards using other types of carriers to improve tumor targeting and to minimize the side effects. One of the approaches is to entrap PS into the lipophilic core of low-d. lipoproteins (LDL) without altering their biol. properties. The LDL receptor pathway is an important factor in the selective accumulation of PS in tumor tissue owing to the increased no. of LDL receptors on the proliferating cell surface. Specific targeting can also be achieved by binding of mAb or specific tumor-seeking mols. to PS or by the coating of PS loaded carriers.88Paszko, E.; Ehrhardt, C.; Senge, M. O.; Kelleher, D. P.; Reynolds, J. V. Nanodrug Applications in Photodynamic Therapy. Photodiagn. Photodyn. Ther. 2011, 8, 14– 29, DOI: 10.1016/j.pdpdt.2010.12.001[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXit1Whsbo%253D&md5=b15fa05ad39cf9451d8b9e898df336feNanodrug applications in photodynamic therapyPaszko, Edyta; Ehrhardt, Carsten; Senge, Mathias O.; Kelleher, Dermot P.; Reynolds, John V.Photodiagnosis and Photodynamic Therapy (2011), 8 (1), 14-29CODEN: PPTHBF; ISSN:1572-1000. (Elsevier B.V.)A review. Photodynamic therapy (PDT) has developed over last century and is now becoming a more widely used medical tool having gained regulatory approval for the treatment of various diseases such as cancer and macular degeneration. It is a two-step technique in which the delivery of a photosensitizing drug is followed by the irradn. of light. Activated photosensitizers transfer energy to mol. oxygen which results in the generation of reactive oxygen species which in turn cause cells apoptosis or necrosis. Although this modality has significantly improved the quality of life and survival time for many cancer patients it still offers significant potential for further improvement. In addn. to the development of new PDT drugs, the use of nanosized carriers for photosensitizers is a promising approach which might improve the efficiency of photodynamic activity and which can overcome many side effects assocd. with classic photodynamic therapy. This review aims at highlighting the different types of nanomedical approaches currently used in PDT and outlines future trends and limitations of nanodelivery of photosensitizers.89Sumer, B.; Gao, J. Theranostic Nanomedicine for Cancer. Nanomedicine 2008, 3, 137– 140, DOI: 10.2217/17435889.3.2.137[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c3hvVCqtw%253D%253D&md5=7f8a40ef7881a2aad40d944e6206ba09Theranostic nanomedicine for cancerSumer Baran; Gao JinmingNanomedicine (London, England) (2008), 3 (2), 137-40 ISSN:.There is no expanded citation for this reference.90Koning, Gerben A.; Krijger, Gerard C. Targeted Multifunctional Lipid-Based Nanocarriers for Image-Guided Drug Delivery. Anti-Cancer Agents Med. Chem. 2007, 7, 425– 440, DOI: 10.2174/187152007781058613[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsV2ht7w%253D&md5=cc0cf32a780485b34373ad2151010e71Targeted multifunctional lipid-based nanocarriers for image-guided drug deliveryKoning, Gerben A.; Krijger, Gerard C.Anti-Cancer Agents in Medicinal Chemistry (2007), 7 (4), 425-440CODEN: AAMCE4; ISSN:1871-5206. (Bentham Science Publishers Ltd.)A review. Lipid-based nanocarriers have proven successful in the delivery of mainly chemotherapeutic agents, and currently they are being applied clin. in the treatment of various types of cancer. These drug delivery systems achieve increased therapeutic efficacy by altering the pharmacokinetics and biodistribution of encapsulated drugs, resulting in decreased drug toxicity and enhanced accumulation in tumor tissue. This increased accumulation is due to the relatively leaky immature vasculature of a tumor. After the clin. relevance of such drug delivery systems was demonstrated, research in this area focused on optimization, both by cell specific targeting and including controlled and triggered release concepts within the carrier. These more advanced targeted nanocarriers in general have clearly shown their potential in various animal tumor models and await clin. application. The development of targeted nanocarriers in which therapeutic and imaging agents are merged into a single carrier will certainly be of importance in the near future. Indeed, scientists active in the field of imaging (e.g. nuclear and magnetic resonance imaging) have already started to exploit nanocarriers for mol. imaging. Image-guided drug delivery using these multifunctional nanocarriers, contg. therapeutic and imaging agents, will ultimately allow for online monitoring of tumor location, tumor targeting levels, intratumoral localization and drug release kinetics prior and during radio- and/or chemotherapeutic treatment. This review describes the current status and challenges in the field of nanocarrier-aided drug delivery and drug targeting and discusses the opportunities of combining imaging probes with these drug carriers and the potential of these multifunctional lipid-based nanocarriers within image-guided drug delivery.91Batista, C. A. S.; Larson, R. G.; Kotov, N. A. Nonadditivity of Nanoparticle Interactions. Science 2015, 350, 1242477, DOI: 10.1126/science.1242477[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28zgtlyhuw%253D%253D&md5=3a751daf926f015f07a371728e0c0df0Nonadditivity of nanoparticle interactionsBatista Carlos A Silvera; Larson Ronald G; Kotov Nicholas AScience (New York, N.Y.) (2015), 350 (6257), 1242477 ISSN:.Understanding interactions between inorganic nanoparticles (NPs) is central to comprehension of self-organization processes and a wide spectrum of physical, chemical, and biological phenomena. However, quantitative description of the interparticle forces is complicated by many obstacles that are not present, or not as severe, for microsize particles (μPs). Here we analyze the sources of these difficulties and chart a course for future research. Such difficulties can be traced to the increased importance of discreteness and fluctuations around NPs (relative to μPs) and to multiscale collective effects. Although these problems can be partially overcome by modifying classical theories for colloidal interactions, such an approach fails to manage the nonadditivity of electrostatic, van der Waals, hydrophobic, and other interactions at the nanoscale. Several heuristic rules identified here can be helpful for discriminating between additive and nonadditive nanoscale systems. Further work on NP interactions would benefit from embracing NPs as strongly correlated reconfigurable systems with diverse physical elements and multiscale coupling processes, which will require new experimental and theoretical tools. Meanwhile, the similarity between the size of medium constituents and NPs makes atomic simulations of their interactions increasingly practical. Evolving experimental tools can stimulate improvement of existing force fields. New scientific opportunities for a better understanding of the electronic origin of classical interactions are converging at the scale of NPs.92Gmeiner, W. H.; Ghosh, S. Nanotechnology for Cancer Treatment. Nanotechnol. Rev. 2014, 3, 111– 122, DOI: 10.1515/ntrev-2013-0013[Crossref], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmsFWktbs%253D&md5=b4b8b2885465ab6dbc871dc61fb5ea5bNanotechnology for cancer treatmentGmeiner, William H.; Ghosh, SupratimNanotechnology Reviews (2014), 3 (2), 111-122CODEN: NRAEE8; ISSN:2191-9097. (Walter de Gruyter GmbH)A review. Nanotechnol. has the potential to increase the selectivity and potency of chem., phys., and biol. approaches for eliciting cancer cell death while minimizing collateral toxicity to nonmalignant cells. Materials on the nanoscale are increasingly being targeted to cancer cells with great specificity through both active and passive targeting. In this review, we summarize recent literature that has broken new ground in the use of nanotechnol. for cancer treatment with an emphasis on targeted drug delivery.93Elias, D. R.; Poloukhtine, A.; Popik, V.; Tsourkas, A. Effect of Ligand Density, Receptor Density, and Nanoparticle Size on Cell Targeting. Nanomedicine 2013, 9, 194– 201, DOI: 10.1016/j.nano.2012.05.015[Crossref], [PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvFCksbc%253D&md5=ee6466c57aaf7f480f68c659116ae696Effect of ligand density, receptor density, and nanoparticle size on cell targetingElias, Drew R.; Poloukhtine, Andrei; Popik, Vladimir; Tsourkas, AndrewNanomedicine (New York, NY, United States) (2013), 9 (2), 194-201CODEN: NANOBF; ISSN:1549-9634. (Elsevier)It is generally accepted that the presentation of multiple ligands on a nanoparticle (NP) surface can improve cell targeting; however, little work has been done to det. whether an optimal ligand d. exists. We have recently developed a site-specific bioconjugation strategy that allows for distinct control of ligand d. on a NP through the combined utilization of expressed protein ligation (EPL) and copper-free click chem. This EPL-Click conjugation strategy was applied to create superparamagnetic iron oxide (SPIO) NPs labeled with HER2/neu targeting affibodies at differing ligand densities. It was discovered that an intermediate ligand d. provided statistically significant improvements in cell binding in comparison with higher and lower ligand densities. This intermediate optimal ligand d. was conserved across NPs with differing hydrodynamic diams., different HER2/neu targeting ligands and also to cells with lower receptor densities. Addnl., an intermediate optimal ligand d. was also evident when NPs were labeled with folic acid. The authors of this study investigated optimal ligand d. with SPIO-based labeling and concluded that intermediate d. appears to have the most optimal labeling properties from the standpoint of its T2* shortening effect.94Sarpaki, S. Investigations into the Radiochemistry of Gallium- and Fluorine-Containing Compounds for Molecular Imaging Applications, Ph.D. Thesis, University of Bath: England, 2018.95Liu, T. W.; MacDonald, T. D.; Jin, C. S.; Gold, J. M.; Bristow, R. G.; Wilson, B. C.; Zheng, G. Inherently Multimodal Nanoparticle-Driven Tracking and Real-Time Delineation of Orthotopic Prostate Tumors and Micrometastases. ACS Nano 2013, 7, 4221– 4232, DOI: 10.1021/nn400669r[ACS Full Text], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltVOnu7o%253D&md5=2100fecc185119f0425fe3c563200a06Inherently Multimodal Nanoparticle-Driven Tracking and Real-Time Delineation of Orthotopic Prostate Tumors and MicrometastasesLiu, Tracy W.; MacDonald, Thomas D.; Jin, Cheng S.; Gold, Joseph M.; Bristow, Robert G.; Wilson, Brian C.; Zheng, GangACS Nano (2013), 7 (5), 4221-4232CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Prostate cancer is the most common cancer among men and the second cause of male cancer-related deaths. There are currently three crit. needs in prostate cancer imaging to personalize cancer treatment: (1) accurate intraprostatic imaging for multiple foci and extra-capsular extent; (2) monitoring local and systemic treatment response and predicting recurrence; and (3) more sensitive imaging of occult prostate cancer bone metastases. Recently, our lab developed porphysomes, inherently multimodal, all-org. nanoparticles with flexible and robust radiochem. Herein, we validate the first in vivo application of 64Cu-porphysomes in clin. relevant orthotopic prostate and bony metastatic cancer models. We demonstrate clear multimodal delineation of orthotopic tumors on both the macro- and the microscopic scales (using both PET and fluorescence) and sensitively detected small bony metastases (<2 mm). The unique and multifaceted properties of porphysomes offers a promising all-in-one prostate cancer imaging agent for tumor detection and treatment response/recurrence monitoring using both radionuclide- and photonic-based strategies.96Mitchell, N.; Kalber, T. L.; Cooper, M. S.; Sunassee, K.; Chalker, S. L.; Shaw, K. P.; Ordidge, K. L.; Badar, A.; Janes, S. M.; Blower, P. J.; Lythgoe, M. F.; Hailes, H. C.; Tabor, A. B. Incorporation of Paramagnetic, Fluorescent and PET/SPECT Contrast Agents Into Liposomes for Multimodal Imaging. Biomaterials 2013, 34, 1179– 1192, DOI: 10.1016/j.biomaterials.2012.09.070[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1WmsLvO&md5=2959ff9de566b6ba5b44236f1cf83b85Incorporation of paramagnetic, fluorescent and PET/SPECT contrast agents into liposomes for multimodal imagingMitchell, Nick; Kalber, Tammy L.; Cooper, Margaret S.; Sunassee, Kavitha; Chalker, Samantha L.; Shaw, Karen P.; Ordidge, Katherine L.; Badar, Adam; Janes, Samuel M.; Blower, Philip J.; Lythgoe, Mark F.; Hailes, Helen C.; Tabor, Alethea B.Biomaterials (2013), 34 (4), 1179-1192CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)A series of metal-chelating lipid conjugates has been designed and synthesized. Each member of the series bears a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) macrocycle attached to the lipid head group, using short n-ethylene glycol (n-EG) spacers of varying length. Liposomes incorporating these lipids, chelated to Gd3+, 64Cu2+, or 111In3+, and also incorporating fluorescent lipids, have been prepd., and their application in optical, magnetic resonance (MR) and single-photon emission tomog. (SPECT) imaging of cellular uptake and distribution investigated in vitro and in vivo. We have shown that these multimodal liposomes can be used as functional MR contrast agents as well as radionuclide tracers for SPECT, and that they can be optimized for each application. When shielded liposomes were formulated incorporating 50% of a lipid with a short n-EG spacer, to give nanoparticles with a shallow but even coverage of n-EG, they showed good cellular internalization in a range of tumor cells, compared to the limited cellular uptake of conventional shielded liposomes formulated with 7% 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethyleneglycol)2000] (DSPE-PEG2000). Moreover, by matching the depth of n-EG coverage to the length of the n-EG spacers of the DOTA lipids, we have shown that similar distributions and blood half lives to DSPE-PEG2000-stabilized liposomes can be achieved. The ability to tune the imaging properties and distribution of these liposomes allows for the future development of a flexible tri-modal imaging agent.97Zhang, R.; Huang, M.; Zhou, M.; Wen, X.; Huang, Q.; Li, C. Annexin A5-Functionalized Nanoparticle for Multimodal Imaging of Cell Death. Mol. Imaging 2013, 12, 7290.2012.00032, DOI: 10.2310/7290.2012.0003298Liu, T. W.; MacDonald, T. D.; Shi, J.; Wilson, B. C.; Zheng, G. Intrinsically Copper-64-Labeled Organic Nanoparticles as Radiotracers. Angew. Chem., Int. Ed. 2012, 51, 13128– 13131, DOI: 10.1002/anie.201206939[Crossref], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1OgtL%252FE&md5=213a0e3475e6210599b4b8b1f55f0e17Intrinsically Copper-64-Labeled Organic Nanoparticles as RadiotracersLiu, Tracy W.; MacDonald, Thomas D.; Shi, Jiyun; Wilson, Brian C.; Zheng, GangAngewandte Chemie, International Edition (2012), 51 (52), 13128-13131CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)An exogenous-chelator-free nanoplatform that has intrinsic capacity for use as a radiotracer is described. Copper-64-porphysomes can delineate diseased tissue in a clin. relevant orthotopic prostate cancer model.99Janib, S. M.; Moses, A. S.; MacKay, J. A. Imaging and Drug Delivery Using Theranostic Nanoparticles. Adv. Drug Delivery Rev. 2010, 62, 1052– 1063, DOI: 10.1016/j.addr.2010.08.004[Crossref], [PubMed], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVGitb7I&md5=40d00066b77a02d636c87b97ccbe404cImaging and drug delivery using theranostic nanoparticlesJanib, Siti M.; Moses, Ara S.; MacKay, J. AndrewAdvanced Drug Delivery Reviews (2010), 62 (11), 1052-1063CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Nanoparticle technologies are significantly impacting the development of both therapeutic and diagnostic agents. At the intersection between treatment and diagnosis, interest has grown in combining both paradigms into clin. effective formulations. This concept, recently coined as theranostics, is highly relevant to agents that target mol. biomarkers of disease and is expected to contribute to personalized medicine. Here the authors review state-of-the-art nanoparticles from a therapeutic and a diagnostic perspective and discuss challenges in bringing these fields together. Major classes of nanoparticles include, drug conjugates and complexes, dendrimers, vesicles, micelles, core-shell particles, microbubbles, and carbon nanotubes. Most of these formulations were described as carriers of either drugs or contrast agents. To observe these formulations and their interactions with disease, a variety of contrast agents were used, including optically active small mols., metals and metal oxides, ultrasonic contrast agents, and radionuclides. The opportunity to rapidly assess and adjust treatment to the needs of the individual offers potential advantages that will spur the development of theranostic agents.100McCarthy, J. R.; Weissleder, R. Multifunctional Magnetic Nanoparticles for Targeted Imaging and Therapy. Adv. Drug Delivery Rev. 2008, 60, 1241– 1251, DOI: 10.1016/j.addr.2008.03.014[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosVOnsr0%253D&md5=625a82ec4cc171ad24f5c6b151853cc8Multifunctional magnetic nanoparticles for targeted imaging and therapyMcCarthy, Jason R.; Weissleder, RalphAdvanced Drug Delivery Reviews (2008), 60 (11), 1241-1251CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Magnetic nanoparticles have become important tools for the imaging of prevalent diseases, such as cancer, atherosclerosis, diabetes, and others. While first generation nanoparticles were fairly nonspecific, newer generations have been targeted to specific cell types and mol. targets via affinity ligands. Commonly, these ligands emerge from phage or small mol. screens, or are based on antibodies or aptamers. Secondary reporters and combined therapeutic mols. have further opened potential clin. applications of these materials. This review summarizes some of the recent biomedical applications of these newer magnetic nanomaterials.101McCarthy, J. R. The Future of Theranostic Nanoagents. Nanomedicine 2009, 4, 693– 695, DOI: 10.2217/nnm.09.58[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1Mjgt1Sguw%253D%253D&md5=7a7b30d1133edd4d46dff3469715bfb9The future of theranostic nanoagentsMcCarthy Jason RNanomedicine (London, England) (2009), 4 (7), 693-5 ISSN:.There is no expanded citation for this reference.102Summer, D.; Grossrubatscher, L.; Petrik, M.; Michalcikova, T.; Novy, Z.; Rangger, C.; Klingler, M.; Haas, H.; Kaeopookum, P.; Von Guggenberg, E.; Haubner, R.; Decristoforo, C. Developing Targeted Hybrid Imaging Probes by Chelator Scaffolding. Bioconjugate Chem. 2017, 28, 1722– 1733, DOI: 10.1021/acs.bioconjchem.7b00182[ACS Full Text], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvFSjtL4%253D&md5=97ec9253bcecf76484667c18772177ccDeveloping Targeted Hybrid Imaging Probes by Chelator ScaffoldingSummer, Dominik; Grossrubatscher, Leo; Petrik, Milos; Michalcikova, Tereza; Novy, Zbynek; Rangger, Christine; Klingler, Maximilian; Haas, Hubertus; Kaeopookum, Piriya; von Guggenberg, Elisabeth; Haubner, Roland; Decristoforo, ClemensBioconjugate Chemistry (2017), 28 (6), 1722-1733CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Positron emission tomog. (PET) as well as optical imaging (OI) with peptide receptor targeting probes have proven their value for oncol. applications but also show restrictions depending on the clin. field of interest. Therefore, the combination of both methods, particularly in a single mol., could improve versatility in clin. routine. This proof of principle study aims to show that a chelator, Fusarinine C (FSC), can be utilized as scaffold for novel dimeric dual-modality imaging agents. Two targeting vectors (a minigastrin analog (MG11) targeting cholecystokinin-2 receptor overexpression (CCK2R) or integrin αVβ3 targeting cyclic pentapeptides (RGD)) and a near-IR fluorophore (Sulfo-Cyanine7) were conjugated to FSC. The probes were efficiently labeled with gallium-68 and in vitro expts. including detn. of logD, stability, protein binding, cell binding, internalization, and biodistribution studies as well as in vivo micro-PET/CT and optical imaging in U-87MG αVβ3- and A431-CCK2R expressing tumor xenografted mice were carried out. Novel bioconjugates showed high receptor affinity and highly specific targeting properties at both receptors. Ex vivo biodistribution and micro-PET/CT imaging studies revealed specific tumor uptake accompanied by slow blood clearance and retention in nontargeted tissues (spleen, liver, and kidneys) leading to visualization of tumors at early (30 to 120 min p.i.). Excellent contrast in corresponding optical imaging studies was achieved esp. at delayed time points (24 to 72 h p.i.). Our findings show the proof of principle of chelator scaffolding for hybrid imaging agents and demonstrate FSC being a suitable bifunctional chelator for this approach. Improvements to fine-tune pharmacokinetics are needed to translate this into a clin. setting.103Iyer, A. K.; Greish, K.; Seki, T.; Okazaki, S.; Fang, J.; Takeshita, K.; Maeda, H. Polymeric Micelles of Zinc Protoporphyrin for Tumor Targeted Delivery Based on EPR Effect and Singlet Oxygen Generation. J. Drug Target. 2007, 15, 496– 506, DOI: 10.1080/10611860701498252[Crossref], [PubMed], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXosVSktL8%253D&md5=1aa4231de184724f8646d1158d7520d6Polymeric micelles of zinc protoporphyrin for tumor targeted delivery based on EPR effect and singlet oxygen generationIyer, Arun K.; Greish, Khaled; Seki, Takahiro; Okazaki, Shoko; Fang, Jun; Takeshita, Keizo; Maeda, HiroshiJournal of Drug Targeting (2007), 15 (7-8), 496-506CODEN: JDTAEH; ISSN:1061-186X. (Informa Healthcare)Polymeric micelles of zinc protoporphyrin (ZnPP) with water sol. biocompatible and amphiphilic polymer, polyethylene glycol (PEG) demonstrated unique characteristics to target tumor tissues selectively based on the enhanced permeability and retention (EPR) effect. The micellar macromol. drug of ZnPP (SMA-ZnPP and PEG-ZnPP) previously showed notable anticancer activity as a consequence of selective tumor targeting ability and its potent HO-1 inhibitory potential, resulting in suppressed biliverdin/bilirubin prodn. in tumors thereby leading to oxystress induced tumor cell killing. Furthermore, recent findings also showed that ZnPP efficiently generated reactive singlet oxygen under illumination of visible light, laser, or xenon light source, which could augment its oxystress induced cell killing abilities. In the present paper, we report the synergistic effects of light induced photosensitizing capabilities and HO-1 inhibitory potentials of these unique micelles when tested in vitro and in vivo on tumor models under localized, mild illumination conditions using a tungsten-xenon light source. The results indicate that these water sol. polymeric micelles of ZnPP portend to be promising candidates for targeted chemotherapy as well as photodynamic therapy against superficial tumors as well as solid tumors located at light penetrable depths.104Maeda, H.; Greish, K.; Fang, J. The EPR Effect and Polymeric Drugs: A Paradigm Shift for Cancer Chemotherapy in the 21st Century. Adv. Polym. Sci. 2005, 193, 103– 121, DOI: 10.1007/12_026105Cai, W.; Chen, X. Multimodality Molecular Imaging of Tumor Angiogenesis. J. Nucl. Med. 2008, 49, 113– 128, DOI: 10.2967/jnumed.107.045922[Crossref], [PubMed], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXotFahu74%253D&md5=23862c321056fbf7ff1dd5b2f011f89dMultimodality molecular imaging of tumor angiogenesisCai, Weibo; Chen, XiaoyuanJournal of Nuclear Medicine (2008), 49 (Suppl. 2), 113S-128SCODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)A review. Mol. imaging is a key component of 21st-century cancer management. The vascular endothelial growth factor (VEGF)/VEGF receptor signaling pathway and integrin αvβ3, a cell adhesion mol., play pivotal roles in regulating tumor angiogenesis, the growth of new blood vessels. This review summarizes the current status of tumor angiogenesis imaging with SPECT, PET, mol. MRI, targeted ultrasound, and optical techniques. For integrin αvβ3 imaging, only nanoparticle-based probes, which truly target the tumor vasculature rather than tumor cells because of poor extravasation, are discussed. Once improvements in the in vivo stability, tumor-targeting efficacy, and pharmacokinetics of tumor angiogenesis imaging probes are made, translation to clin. applications will be crit. for the max. benefit of these novel agents. The future of tumor angiogenesis imaging lies in multimodality and nanoparticle-based approaches, imaging of protein-protein interactions, and quant. mol. imaging. Combinations of multiple modalities can yield complementary information and offer synergistic advantages over any modality alone. Nanoparticles, possessing multifunctionality and enormous flexibility, can allow for the integration of therapeutic components, targeting ligands, and multimodality imaging labels into one entity, termed "nano-medicine," for which the ideal target is tumor neovasculature. Quant. imaging of tumor angiogenesis and protein-protein interactions that modulate angiogenesis will lead to more robust and effective monitoring of personalized mol. cancer therapy. Multidisciplinary approaches and cooperative efforts from many individuals, institutions, industries, and organizations are needed to quickly translate multimodality tumor angiogenesis imaging into multiple facets of cancer management. Not limited to cancer, these novel agents can also have broad applications for many other angiogenesis-related diseases.106Haglund, E.; Seale-Goldsmith, M. M.; Leary, J. F. Design of Multifunctional Nanomedical Systems. Ann. Biomed. Eng. 2009, 37, 2048– 2063, DOI: 10.1007/s10439-009-9640-2[Crossref], [PubMed], [CAS], Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MnitlKnsg%253D%253D&md5=90b7835e0e12088f22a33fc54cb7fee6Design of multifunctional nanomedical systemsHaglund E; Seale-Goldsmith M-M; Leary J FAnnals of biomedical engineering (2009), 37 (10), 2048-63 ISSN:.Multifunctional nanoparticles hold great promise for drug/gene delivery and simultaneous diagnostics and therapeutics ("theragnostics") including use of core materials that provide in vivo imaging and opportunities for externally modulated therapeutic interventions. Multilayered nanoparticles can act as nanomedical systems with on-board molecular programming done through the chemistry of highly specialized layers to accomplish complex and potentially decision-making tasks. The targeting process itself is a multi-step process consisting of initial cell recognition through cell surface receptors, cell entry through the membrane in a manner to prevent undesired alterations of the nanomedical system, re-targeting to the appropriate sub-region of the cell where the therapeutic package can be localized, and potentially control of that therapeutic process through feedback systems using molecular biosensors. This paper describes a bionanoengineering design process in which sophisticated nanomedical platform systems can be designed for diagnosis and treatment of disease. The feasibility of most of these subsystems has been demonstrated, but the full integration of these interacting sub-components remains a challenge for the field. Specific examples of sub-components developed for specific applications are described.107Svenskaya, Y.; Parakhonskiy, B.; Haase, A.; Atkin, V.; Lukyanets, E.; Gorin, D.; Antolini, R. Anticancer Drug Delivery System Based on Calcium Carbonate Particles Loaded with a Photosensitizer. Biophys. Chem. 2013, 182, 11– 15, DOI: 10.1016/j.bpc.2013.07.006[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Cqu7zJ&md5=d18176b764ebfa127352eb7a92d6d1e8Anticancer drug delivery system based on calcium carbonate particles loaded with a photosensitizerSvenskaya, Yulia; Parakhonskiy, Bogdan; Haase, Albrecht; Atkin, Vsevolod; Lukyanets, Evgeny; Gorin, Dmitry; Antolini, RenzoBiophysical Chemistry (2013), 182 (), 11-15CODEN: BICIAZ; ISSN:0301-4622. (Elsevier B.V.)In photodynamic therapy (PDT), photosensitizers are required to arrive in high concns. at selective targets like cancer cells avoiding toxicity in healthy tissue. In this work, the authors propose the application of porous calcium carbonate carriers in the form of polycryst. vaterite for this task. The authors investigated the loading efficiency for the photosensitizer Photosens in vaterite micro- and nanocarriers. A possible release mechanism depending on the surrounding pH was studied, showing a fast degrdn. of the carriers in buffers below pH 7. These results hold out the prospect of a novel PDT drug delivery system. Variation of particle size or addnl. coatings allow custom-design of workload release curves. An intrinsic cancer-sensitivity can be expected from the pH-dependent release in the acidic microenvironment of cancer tissue.108Cheng, L.; Wang, C.; Feng, L.; Yang, K.; Liu, Z. Functional Nanomaterials for Phototherapies of Cancer. Chem. Rev. 2014, 114, 10869– 10939, DOI: 10.1021/cr400532z[ACS Full Text], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1eju7zP&md5=ef0626bcbe29036570f427034d5c8658Functional Nanomaterials for Phototherapies of CancerCheng, Liang; Wang, Chao; Feng, Liangzhu; Yang, Kai; Liu, ZhuangChemical Reviews (Washington, DC, United States) (2014), 114 (21), 10869-10939CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review.109Ding, D.; Guo, W.; Guo, C.; Sun, J.; Zheng, N.; Wang, F.; Yan, M.; Liu, S. MoO3-X Quantum Dots for Photoacoustic Imaging Guided Photothermal/Photodynamic Cancer Treatment. Nanoscale 2017, 9, 2020– 2029, DOI: 10.1039/C6NR09046J[Crossref], [PubMed], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkvVWitg%253D%253D&md5=00f6a3fd550dd12f73bd8fc33215ea61MoO3-x quantum dots for photoacoustic imaging guided photothermal/photodynamic cancer treatmentDing, Dandan; Guo, Wei; Guo, Chongshen; Sun, Jianzhe; Zheng, Nannan; Wang, Fei; Yan, Mei; Liu, ShaoqinNanoscale (2017), 9 (5), 2020-2029CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)A theranostic system of image-guided phototherapy is considered as a potential technique for cancer treatment because of the ability to integrate diagnostics and therapies together, thus enhancing accuracy and visualization during the treatment. In this work, we realized photoacoustic (PA) imaging-guided photothermal (PT)/photodynamic (PD) combined cancer treatment just via a single material, MoO3-x quantum dots (QDs). Due to their strong NIR harvesting ability, MoO3-x QDs can convert incident light into hyperthermia and sensitize the formation of singlet oxygen synchronously as evidenced by in vitro assay, hence, they can behave as both PT and PD agents effectively and act as a "dual-punch" to cancer cells. In a further study, elimination of solid tumors from HeLa-tumor bearing mice could be achieved in a MoO3-x QD mediated phototherapeutic group without obvious lesions to the major organs. In addn., the desired PT effect also makes MoO3-x QDs an exogenous PA contrast agent for in vivo live-imaging to depict tumors. Compared with previously reported theranostic systems that put several components into one system, our multifunctional agent of MoO3-x QDs is exempt from unpredictable mutual interference between components and ease of leakage of virtual components from the composited system.110Lu, K.; He, C.; Lin, W. Nanoscale Metal-Organic Framework for Highly Effective Photodynamic Therapy of Resistant Head and Neck Cancer. J. Am. Chem. Soc. 2014, 136, 16712– 16715, DOI: 10.1021/ja508679h[ACS Full Text], [CAS], Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFCisbjL&md5=8187bb3f17e2feab3346ebef74a2cbe8Nanoscale Metal-Organic Framework for Highly Effective Photodynamic Therapy of Resistant Head and Neck CancerLu, Kuangda; He, Chunbai; Lin, WenbinJournal of the American Chemical Society (2014), 136 (48), 16712-16715CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Photodynamic therapy (PDT) is an effective anticancer procedure that relies on tumor localization of a photosensitizer followed by light activation to generate cytotoxic reactive oxygen species (e.g., 1O2). Here we report the rational design of a Hf-porphyrin nanoscale metal-org. framework, DBP-UiO, as an exceptionally effective photosensitizer for PDT of resistant head and neck cancer. DBP-UiO efficiently generates 1O2 owing to site isolation of porphyrin ligands, enhanced intersystem crossing by heavy Hf centers, and facile 1O2 diffusion through porous DBP-UiO nanoplates. Consequently, DBP-UiO displayed greatly enhanced PDT efficacy both in vitro and in vivo, leading to complete tumor eradication in half of the mice receiving a single DBP-UiO dose and a single light exposure. NMOFs thus represent a new class of highly potent PDT agents and hold great promise in treating resistant cancers in the clinic.111Liu, J.; Yang, Y.; Zhu, W.; Yi, X.; Dong, Z.; Xu, X.; Chen, M.; Yang, K.; Lu, G.; Jiang, L.; Liu, Z. Nanoscale Metal-Organic Frameworks for Combined Photodynamic & Radiation Therapy in Cancer Treatment. Biomaterials 2016, 97, 1– 9, DOI: 10.1016/j.biomaterials.2016.04.034[Crossref], [PubMed], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmvFyhsbg%253D&md5=120b3e903c33466876743b04dcc8f427Nanoscale metal-organic frameworks for combined photodynamic & radiation therapy in cancer treatmentLiu, Jingjing; Yang, Yu; Zhu, Wenwen; Yi, Xuan; Dong, Ziliang; Xu, Xiaona; Chen, Meiwan; Yang, Kai; Lu, Guang; Jiang, Lixin; Liu, ZhuangBiomaterials (2016), 97 (), 1-9CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Nanoscale metal org. frameworks (NMOFs) have shown great potential in biomedicine owing to their structural/chem. diversities, high mol. loading capacities, and intrinsic biodegradability. Herein, we report the rational design of a NMOF composed by hafnium (Hf4+) and tetrakis (4-carboxyphenyl) porphyrin (TCPP). In such Hf-TCPP NMOFs, while TCPP is a photosensitizer to allow photodynamic therapy (PDT), Hf4+ with strong X-ray attenuation ability could serve as a radio-sensitizer to enhance radiotherapy (RT). Those NMOFs with polyethylene glycol (PEG) coating show efficient tumor homing upon i.v. injection, and thus could be used for in vivo combined RT & PDT, achieving a remarkable anti-tumor effect. Importantly, Hf-TCPP NMOFs show efficient clearance from the mouse body, minimizing concerns regarding their possible long-term toxicity. Our work thus presents a new concept of developing multifunctional NMOFs as a biodegradable carrier-free system, in which both metal ions and org. ligands are fully utilized to exert their therapeutic functions.112Sansaloni-Pastor, S.; Bouilloux, J.; Lange, N. The Dark Side: Photosensitizer Prodrugs. Pharmaceuticals 2019, 12 (4), 148, DOI: 10.3390/ph12040148[Crossref], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhslaltrfO&md5=a81700e60f4ecb905c932b9692611e86The dark side: photosensitizer prodrugsSansaloni-Pastor, Sara; Bouilloux, Jordan; Lange, NorbertPharmaceuticals (2019), 12 (4), 148CODEN: PHARH2; ISSN:1424-8247. (MDPI AG)A review. Photodynamic therapy (PDT) and photodiagnosis (PD) are essential approaches in the field of biophotonics. Ideally, both modalities require the selective sensitization of the targeted disease in order to avoid undesired phenomena such as the destruction of healthy tissue, skin photosensitization, or mistaken diagnosis. To a large extent, the occurrence of these incidents can be attributed to "background" accumulation in non-target tissue. Therefore, an ideal photoactive compd. should be optically silent in the absence of disease, but bright in its presence. Such requirements can be fulfilled using innovative prodrug strategies targeting disease-assocd. alterations. Here we will summarize the elaboration, characterization, and evaluation of approaches using polymeric photosensitizer prodrugs, nanoparticles, micelles, and porphysomes. Finally, we will discuss the use of 5-aminolevulinic acid and its derivs. that are selectively transformed in neoplastic cells into photoactive protoporphyrin IX.113Lovell, J. F.; Jin, C. S.; Huynh, E.; Jin, H.; Kim, C.; Rubinstein, J. L.; Chan, W. C. W.; Cao, W.; Wang, L. V.; Zheng, G. Porphysome Nanovesicles Generated by Porphyrin Bilayers for Use as Multimodal Biophotonic Contrast Agents. Nat. Mater. 2011, 10, 324– 332, DOI: 10.1038/nmat2986[Crossref], [PubMed], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjvVGjtLk%253D&md5=a49010fc6bd9ff369fd0e814ba59bdfaPorphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agentsLovell, Jonathan F.; Jin, Cheng S.; Huynh, Elizabeth; Jin, Honglin; Kim, Chulhong; Rubinstein, John L.; Chan, Warren C. W.; Cao, Weiguo; Wang, Lihong V.; Zheng, GangNature Materials (2011), 10 (4), 324-332CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)Optically active nanomaterials promise to advance a range of biophotonic techniques through nanoscale optical effects and integration of multiple imaging and therapeutic modalities. Here, we report the development of porphysomes; nanovesicles formed from self-assembled porphyrin bilayers that generated large, tunable extinction coeffs., structure-dependent fluorescence self-quenching and unique photothermal and photoacoustic properties. Porphysomes enabled the sensitive visualization of lymphatic systems using photoacoustic tomog. Near-IR fluorescence generation could be restored on dissocn., creating opportunities for low-background fluorescence imaging. As a result of their org. nature, porphysomes were enzymically biodegradable and induced minimal acute toxicity in mice with i.v. doses of 1000 mg kg-1. In a similar manner to liposomes, the large aq. core of porphysomes could be passively or actively loaded. Following systemic administration, porphysomes accumulated in tumors of xenograft-bearing mice and laser irradn. induced photothermal tumor ablation. The optical properties and biocompatibility of porphysomes demonstrate the multimodal potential of org. nanoparticles for biophotonic imaging and therapy.114Waghorn, P. A. Radiolabelled Porphyrins in Nuclear Medicine. J. Labelled Compd. Radiopharm. 2014, 57, 304– 309, DOI: 10.1002/jlcr.3166[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFGitLzN&md5=f3aad472c2742db5b76c63f7a1608e68Radiolabelled porphyrins in nuclear medicineWaghorn, Philip A.Journal of Labelled Compounds and Radiopharmaceuticals (2014), 57 (4), 304-309CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)A review. Amongst tumor-specific substances, hematoporphyrin and synthetic porphyrin derivs. have been widely investigated to identify and delineate neoplastic and malignant tissue. While the tumor localization exhibited by selected porphyrin species has been exploited through photodynamic therapy, several examples of porphyrin derivs. with varied peripheral functionality have been radiolabeled with the aim of developing porphyrin-based nuclear imaging and therapeutic agents. In this review, we look at the approaches and advances in the prepn. and uses of such radiolabeled agents for imaging and therapy. Copyright © 2013 John Wiley & Sons, Ltd.115Ng, K. K.; Takada, M.; Jin, C. C. S.; Zheng, G. Self-Sensing Porphysomes for Fluorescence-Guided Photothermal Therapy. Bioconjugate Chem. 2015, 26, 345– 351, DOI: 10.1021/bc500595d[ACS Full Text], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXktFWiug%253D%253D&md5=bea714b9dea2842eb3a59b82eb6b986fSelf-Sensing Porphysomes for Fluorescence-Guided Photothermal TherapyNg, Kenneth K.; Takada, Misa; Jin, Cheng C. S.; Zheng, GangBioconjugate Chemistry (2015), 26 (2), 345-351CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Porphysomes are highly quenched unilamellar porphyrin-lipid nanovesicles with structurally dependent photothermal properties. The high packing d. of porphyrin mols. in the lipid bilayer enables their application in photothermal therapy, whereas the partial disruption of the porphysome structure over time restores the porphyrin fluorescence and enables the fluorescence-guided photothermal ablation. This conversion is a time-dependent process and cannot be easily followed using existing anal. techniques. Here we present the design of a novel self-sensing porphysome (FRETysomes) capable of fluorescently broadcasting its structural state through Foddorster resonance energy transfer. By doping in a near-IR emitting fluorophore, it is possible to divert a small fraction of the absorbed energy toward fluorescence emission which provides information on whether the vesicle is intact or disrupted. Addn. of bacteriopheophorbide-lipid into the vesicle bilayer as a fluorescence acceptor (0.5-7.5 mol %) yields a large sepn. of 100 nm between the absorption and fluorescence bands of the nanoparticle. Furthermore, a progressive increase in FRET efficiency (14.6-72.7%) is obsd. Photothermal heating and serum stability in FRETysomes is comparable with the undoped porphysomes. The fluorescence arising from the energy transfer between the donor and acceptor dyes can be clearly visualized in vivo through hyperspectral imaging. By calcg. the ratio between the acceptor and donor fluorescence, it is possible to det. the structural fate of the nanovesicles. We observe using this technique that tumor accumulation of structurally intact porphyrin-lipid nanovesicles persists at 24 and 48 h postinjection. The development of FRETysomes offers a unique and crit. imaging tool for planning porphysome-enabled fluorescence-guided photothermal treatment, which maximizes light-induced thermal toxicity.116Allison, R. R.; Bagnato, V. S.; Sibata, C. H. Future of Oncologic Photodynamic Therapy. Future Oncol. 2010, 6, 929– 940, DOI: 10.2217/fon.10.51[Crossref], [PubMed], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXntFGitb4%253D&md5=61c462de57f6e3a2921e33fa576c7f97Future of oncologic photodynamic therapyAllison, Ron R.; Bagnato, Vanderlei S.; Sibata, Claudio H.Future Oncology (2010), 6 (6), 929-940CODEN: FOUNBN; ISSN:1479-6694. (Future Medicine Ltd.)A review. Photodynamic therapy (PDT) is a tumor-ablative and function-sparing oncol. intervention. The relative simplicity of photosensitizer application followed by light activation resulting in the cytotoxic and vasculartoxic photodynamic reaction has allowed PDT to reach a worldwide audience. With several com. available photosensitizing agents now on the market, numerous well designed clin. trials have demonstrated the efficacy of PDT on various cutaneous and deep tissue tumors. However, current photosensitizers and light sources still have a no. of limitations. Future PDT will build on those findings to allow development and refinement of more optimal therapeutic agents and illumination devices. This article reviews the current state of the art and limitations of PDT, and highlight the progress being made towards the future of oncol. PDT.117Wieder, M. E.; Hone, D. C.; Cook, M. J.; Handsley, M. M.; Gavrilovic, J.; Russell, D. A. Intracellular Photodynamic Therapy With Photosensitizer-Nanoparticle Conjugates: Cancer Therapy Using a ‘Trojan Horse.’. Photochem. Photobiol. Sci. 2006, 5, 727– 734, DOI: 10.1039/B602830F[Crossref], [PubMed], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XnslKqu7o%253D&md5=40df9e5ebd1001ef71dc457acd3cc340Intracellular photodynamic therapy with photosensitizer-nanoparticle conjugates: cancer therapy using a 'Trojan horse'Wieder, Martina E.; Hone, Duncan C.; Cook, Michael J.; Handsley, Madeleine M.; Gavrilovic, Jelena; Russell, David A.Photochemical & Photobiological Sciences (2006), 5 (8), 727-734CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)Phthalocyanine-nanoparticle conjugates have been designed and synthesized for the delivery of hydrophobic photosensitizers for photodynamic therapy (PDT) of cancer. The phthalocyanine photosensitizer stabilized gold nanoparticles have an av. diam. of 2-4 nm. The synthetic strategy interdigitates a phase transfer reagent between phthalocyanine mols. on the particle surface that solubilizes the hydrophobic photosensitizer in polar solvents enabling delivery of the nanoparticle conjugates to cells. The phthalocyanine is present in the monomeric form on the nanoparticle surface, absorbs radiation maximally at 695 nm and catalytically produces the cytotoxic species singlet oxygen with high efficiency. These properties suggest that the phthalocyanine-nanoparticle conjugates are ideally suited for PDT. In a process that can be considered as cancer therapy using a 'Trojan horse', when the nanoparticle conjugates are incubated with HeLa cells (a cervical cancer cell line), they are taken up thus delivering the phthalocyanine photosensitizer directly into the cell interior. Irradn. of the nanoparticle conjugates within the HeLa cells induced substantial cell mortality through the photodynamic prodn. of singlet oxygen. The PDT efficiency of the nanoparticle conjugates, detd. using colorimetric assay, was twice that obtained using the free phthalocyanine deriv. Following PDT with the nanoparticle conjugates, morphol. changes to the HeLa cellular structure were indicative of cell mortality via apoptosis. Further evidence of apoptosis was provided through the bioluminescent assay detection of caspase 3/7. Our results suggest that gold nanoparticle conjugates are an excellent vehicle for the delivery of surface bound hydrophobic photosensitizers for efficacious photodynamic therapy of cultured tumor cells.118Samia, A. C. S.; Chen, X.; Burda, C. Semiconductor Quantum Dots for Photodynamic Therapy. J. Am. Chem. Soc. 2003, 125, 15736– 15737, DOI: 10.1021/ja0386905[ACS Full Text], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXps1Whu70%253D&md5=e0c100daf34d18c8d9a91c2371742fc6Semiconductor quantum dots for photodynamic therapySamia, Anna C. S.; Chen, Xiaobo; Burda, ClemensJournal of the American Chemical Society (2003), 125 (51), 15736-15737CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The applicability of semiconductor QDs in photodynamic therapy (PDT) was evaluated by studying the interaction between CdSe QDs with a known silicon phthalocyanine PDT photosensitizer, Pc4. The study revealed that the QDs could be used to sensitize the PDT agent through a fluorescence resonance energy transfer (FRET) mechanism, or interact directly with mol. oxygen via a triplet energy-transfer process (TET). Both mechanisms result in the generation of reactive singlet oxygen species that can be used for PDT cancer therapy.119Jaiswal, J. K.; Mattoussi, H.; Mauro, J. M.; Simon, S. M. Long-Term Multiple Color Imaging of Live Cells Using Quantum Dot Bioconjugates. Nat. Biotechnol. 2003, 21, 47– 51, DOI: 10.1038/nbt767[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhvVyq&md5=fa97be979d4d5fae784e7239cb6a164eLong-term multiple color imaging of live cells using quantum dot bioconjugatesJaiswal, Jyoti K.; Mattoussi, Hedi; Mauro, J. Matthew; Simon, Sanford M.Nature Biotechnology (2003), 21 (1), 47-51CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)Luminescent quantum dots (QDs)-semiconductor nanocrystals-are a promising alternative to org. dyes for fluorescence-based applications. We have developed procedures for using QDs to label live cells and have demonstrated their use for long-term multicolor imaging of live cells. The two approaches presented are (i) endocytic uptake of QDs and (ii) selective labeling of cell surface proteins with QDs conjugated to antibodies. Live cells labeled using these approaches were used for long-term multicolor imaging. The cells remained stably labeled for over a week as they grew and developed. These approaches should permit the simultaneous study of multiple cells over long periods of time as they proceed through growth and development.120Lira, R. B.; Seabra, M. A. B. L.; Matos, A. L. L.; Vasconcelos, J. V.; Bezerra, D. P.; De Paula, E.; Santos, B. S.; Fontes, A. Studies on Intracellular Delivery of Carboxyl-Coated CdTe Quantum Dots Mediated by Fusogenic Liposomes. J. Mater. Chem. B 2013, 1, 4297– 4305, DOI: 10.1039/c3tb20245c[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1ent77K&md5=873ff92011ddf9ea0d7a4bedc91dbc0aStudies on intracellular delivery of carboxyl-coated CdTe quantum dots mediated by fusogenic liposomesLira, Rafael B.; Seabra, Maria A. B. L.; Matos, Anna L. L.; Vasconcelos, Jessica V.; Bezerra, Darlene P.; de Paula, Eneida; Santos, Beate S.; Fontes, AdrianaJournal of Materials Chemistry B: Materials for Biology and Medicine (2013), 1 (34), 4297-4305CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)The use of Quantum Dots (QDs) as fluorescent probes for understanding biol. functions has emerged as an advantageous alternative over application of conventional fluorescent dyes. Intracellular delivery of QDs is currently a specific field of research. When QDs are tracking a specific target in live cells, they are mostly applied for extracellular membrane labeling. In order to study intracellular mols. and structures it is necessary to deliver free QDs into the cell cytosol. In this work, we adapted the freeze and thaw method to encapsulate water dispersed carboxyl-coated CdTe QDs into liposomes of different compns., including cationic liposomes with fusogenic properties. We showed that labeled liposomes were able to fuse with live human stem cells and red blood cells in an endocytic-independent way. We followed the interactions of liposomes contg. QDs with the cells. The results were minutely discussed and showed that QDs were delivered, but they were not freely diffused in the cytosol of those cells. We believe that this approach has the potential to be applied as a general route for encapsulation and delivery of any membrane-impermeant material into living cells.121Jhonsi, M. A.; Renganathan, R. Investigations on the Photoinduced Interaction of Water Soluble Thioglycolic Acid (TGA) Capped CdTe Quantum Dots with Certain Porphyrins. J. Colloid Interface Sci. 2010, 344, 596– 602, DOI: 10.1016/j.jcis.2010.01.022[Crossref], [PubMed], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtFKjtLk%253D&md5=146638ce52524c4ca37567d8411a6e58Investigations on the photoinduced interaction of water soluble thioglycolic acid (TGA) capped CdTe quantum dots with certain porphyrinsJhonsi, M. Asha; Renganathan, R.Journal of Colloid and Interface Science (2010), 344 (2), 596-602CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)The photoinduced interaction of TGA capped CdTe quantum dots (QDs) with porphyrins such as meso-tetrakis(4-sulfonatophenyl)porphyrin [TSPP], meso-tetrakis(4-carboxyphenyl)porphyrin [TCPP], meso-tetrakis (4-N-methylpyridyl)porphyrin [TMPyP] and meso-tetraphenylporphyrin [TPP] has been studied by using absorption, steady state and time resolved fluorescence spectroscopy. The QD surface was neg. charged due to thiol capping agent contg. carboxylic group. Pos. charged TMPyP interacts with QDs through charge transfer mechanism, neg. charged porphyrins (TCPP and TSPP) interacted through energy transfer mechanism and the neutral one (TPP) does not have any interaction. The Stern-Volmer const., quenching rate const., assocn. consts., rate of electron transfer and energy transfer parameters were calcd. from the fluorescence data. Effect of mol. structure has also been studied.122Li, L.; Zhao, J. F.; Won, N.; Jin, H.; Kim, S.; Chen, J. Y. Quantum Dot - Aluminum Phthalocyanine Conjugates Perform Photodynamic Reactions to Kill Cancer Cells via Fluorescence Resonance Energy Transfer (FRET). Nanoscale Res. Lett. 2012, 7, 386, DOI: 10.1186/1556-276X-7-386[Crossref], [PubMed], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38jpt1SjsQ%253D%253D&md5=4a965385e756a43a7995148104c8a06eQuantum dot-aluminum phthalocyanine conjugates perform photodynamic reactions to kill cancer cells via fluorescence resonance energy transferLi Lei; Zhao Jin-Feng; Won Nayoun; Jin Ho; Kim Sungjee; Chen Ji-YaoNanoscale research letters (2012), 7 (1), 386 ISSN:.Sulfonated aluminum phthalocyanines (AlPcSs), commonly used photosensitizers for photodynamic therapy of cancers (PDT), were conjugated with amine-dihydrolipoic acid-coated quantum dots (QDs) by electrostatic binding, achieving 70 AlPcSs per QD. The AlPcS-QD conjugates can utilize the intense light absorptions of conjugated QDs to indirectly excite AlPcSs producing singlet oxygen via fluorescence resonance energy transfer (FRET), demonstrating a new excitation model for PDT. The AlPcS-QD conjugates easily penetrated into human nasopharyngeal carcinoma cells and carried out the FRET in cells, with efficiency around 80%. Under the irradiation of a 532-nm laser, which is at the absorption region of QDs but not fit for the absorption of AlPcSs, the cellular AlPcS-QD conjugates can destroy most cancer cells via FRET-mediated PDT, showing the potential of this new strategy for PDT.123Rakovich, A.; Savateeva, D.; Rakovich, T.; Donegan, J. F.; Rakovich, Y. P.; Kelly, V.; Lesnyak, V.; Eychmüller, A. CdTe Quantum Dot/Dye Hybrid System as Photosensitizer for Photodynamic Therapy. Nanoscale Res. Lett. 2010, 5, 753– 760, DOI: 10.1007/s11671-010-9553-x[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkvFSmsrg%253D&md5=8ad8265f7fc4dbd95fab73e576142b15CdTe quantum dot/dye hybrid system as photosensitizer for photodynamic therapyRakovich, Aliaksandra; Savateeva, Diana; Rakovich, Tatsiana; Donegan, John F.; Rakovich, Yury P.; Kelly, Vincent; Lesnyak, Vladimir; Eychmuller, AlexanderNanoscale Research Letters (2010), 5 (4), 753-760CODEN: NRLAAD; ISSN:1556-276X. (Springer)We have studied the photodynamic properties of novel CdTe quantum dots - methylene blue hybrid photosensitizer. Absorption spectroscopy, photoluminescence spectroscopy, and fluorescence lifetime imaging of this system reveal efficient charge transfer between nanocrystals and the methylene blue dye. Near-IR photoluminescence measurements provide evidence for an increased efficiency of singlet oxygen prodn. by the methylene blue dye. In vitro studies on the growth of HepG2 and HeLa cancerous cells were also performed, they point toward an improvement in the cell kill efficiency for the methylene blue-semiconductor nanocrystals hybrid system.124Tsay, J. M.; Trzoss, M.; Shi, L.; Kong, X.; Selke, M.; Jung, M. E.; Weiss, S. Singlet Oxygen Production by Peptide-Coated Quantum Dot-Photosensitizer Conjugates. J. Am. Chem. Soc. 2007, 129, 6865– 6871, DOI: 10.1021/ja070713i[ACS Full Text], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkvVClur4%253D&md5=10abb71383dcfd2921547eb262eade8eSinglet Oxygen Production by Peptide-Coated Quantum Dot-Photosensitizer ConjugatesTsay, James M.; Trzoss, Michael; Shi, Lixin; Kong, Xiangxu; Selke, Matthias; Jung, Michael E.; Weiss, ShimonJournal of the American Chemical Society (2007), 129 (21), 6865-6871CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Peptide-coated quantum dot-photosensitizer conjugates were developed using novel covalent conjugation strategies on peptides which overcoat quantum dots (QDs). Rose bengal and chlorin e6, photosensitizers (PSs) that generate singlet oxygen in high yield, were covalently attached to phytochelatin-related peptides. The photosensitizer-peptide conjugates were subsequently used to overcoat green- and red-emitting CdSe/CdS/ZnS nanocrystals. Generation of singlet oxygen could be achieved via indirect excitation through F.ovrddot.orster (fluorescence) resonance energy transfer (FRET) from the nanocrystals to PSs, or by direct excitation of the PSs. In the latter case, by using two color excitations, the conjugate could be simultaneously used for fluorescence imaging and singlet oxygen generation. Singlet oxygen quantum yields as high as 0.31 were achieved using 532-nm excitation wavelengths.125Wen, Y. N.; Song, W. S.; An, L. M.; Liu, Y. Q.; Wang, Y. H.; Yang, Y. Q. Activation of Porphyrin Photosensitizers by Semiconductor Quantum Dots via Two-Photon Excitation. Appl. Phys. Lett. 2009, 95, 143702, DOI: 10.1063/1.3243979[Crossref], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1Cns7vL&md5=de1a09eeb6b7e79d0bfb0525884526e5Activation of porphyrin photosensitizers by semiconductor quantum dots via two-photon excitationWen, Ya-Nan; Song, Wei-Si; An, Li-Min; Liu, Yu-Qiang; Wang, Ying-Hui; Yang, Yan-QiangApplied Physics Letters (2009), 95 (14), 143702/1-143702/3CODEN: APPLAB; ISSN:0003-6951. (American Institute of Physics)Energy transfer from water-sol. quantum dots (QDs) to porphyrinlike sensitizers is studied by time-resolved spectroscopy of two-photon excitation with femtosecond laser pulses. Evident transfer results are obsd. Electron exchange is found to be the dominant transfer mechanism. Relative intensity change between excitonic and trapping emission implies that nonradiative energy transfer occurs through the trapping state of QDs, which presents a way of raising energy transfer efficiency in this type of donor-acceptor pairs. This study underlines the potential of QD-porphyrin model system for applications in two-photon excitation photodynamic therapy. (c) 2009 American Institute of Physics.126Chen, J. Y.; Lee, Y. M.; Zhao, D.; Mak, N. K.; Wong, R. N. S.; Chan, W. H.; Cheung, N. H. Quantum Dot-Mediated Photoproduction of Reactive Oxygen Species for Cancer Cell Annihilation. Photochem. Photobiol. 2010, 86, 431– 437, DOI: 10.1111/j.1751-1097.2009.00652.x[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXotFGqtbg%253D&md5=4800f7186be5a66809b9b85acd023072Quantum dot-mediated photoproduction of reactive oxygen species for cancer cell annihilationChen, Ji-Yao; Lee, Yee-Man; Zhao, Dan; Mak, Nai-Ki; Wong, Ricky Ngok-Shun; Chan, Wing-Hong; Cheung, Nai-HoPhotochemistry and Photobiology (2010), 86 (2), 431-437CODEN: PHCBAP; ISSN:0031-8655. (Wiley-Blackwell)While semiconductor quantum dots produce little singlet oxygen, they may undergo Type I photoreactions to produce other reactive oxygen species (ROS) to kill cells. CdTe quantum dots coated with thioglycolic acid were used to test that possibility. Some thiol ligands were purposely removed to regenerate the surface electron traps that were passivated by the ligand. This allowed photoinduced electrons to dwell on the surface long enough to be gathered by nearby oxygen mols. to produce ROS. The photocytotoxicity of these quantum dots was tested on nasopharyngeal carcinoma cells. Photokilling was shown to be drug and light dose dependent. Using 0.6 μM quantum dots for incubation and 4.8 J cm-2 for irradn., about 80% of the cells were annihilated. These quantum dots promised to be potent sensitizers for photoannihilation of cancer cells.127Wang, R. gui; Zhao, M. yao; Deng, D.; Ye, X.; Zhang, F.; Chen, H.; Kong, J. lie An Intelligent and Biocompatible Photosensitizer Conjugated Silicon Quantum Dots-MnO2 Nanosystem for Fluorescence Imaging-Guided Efficient Photodynamic Therapy. J. Mater. Chem. B 2018, 6, 4592– 4601, DOI: 10.1039/C8TB00931G[Crossref], [PubMed], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFGgtL7N&md5=3b97c69421eba41ee77e79de96f4479cAn intelligent and biocompatible photosensitizer conjugated silicon quantum dots-MnO2 nanosystem for fluorescence imaging-guided efficient photodynamic therapyWang, Rong-gui; Zhao, Meng-yao; Deng, Di; Ye, Xin; Zhang, Fan; Chen, Hui; Kong, Ji-lieJournal of Materials Chemistry B: Materials for Biology and Medicine (2018), 6 (28), 4592-4601CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)Photodynamic therapy (PDT) has been widely applied in cancer treatment due to minimal invasion, negligible side effects and specific tumor ablation. However, the treatment efficiency has been hindered by hypoxia in solid tumors, hydrophobic photosensitizers and their real time tracking. In this paper, we constructed an intelligent and biocompatible bovine serum albumin (BSA)-Ce6-Si QDs-MnO2 (BCSM NPs) nanocomplex as a pH/H2O2 responsive photosensitizer nanocarrier to modulate tumor hypoxia for fluorescence imaging-guided efficient PDT. This versatile nanosystem not only enhanced the loading capacity of the photosensitizer and the formation of cytotoxic singlet oxygen (1O2) owing to the intelligent prodn. of oxygen catalyzed by MnO2 from the endogenous H2O2, but also performed as a dual functional fluorescence and Magnetic Resonance imaging (MRI) probe. In vivo expts. in nude mice further confirmed that BCSM NPs significantly inhibited the growth of HeLa bearing-tumors compared to free Ce6. The results highlight the great potentail of multifunctional BCSM NPs for in vivo imaging as well as enhancing the photodynamic therapy efficiency.128Biju, V.; Itoh, T.; Ishikawa, M. Delivering Quantum Dots to Cells: Bioconjugated Quantum Dots for Targeted and Nonspecific Extracellular and Intracellular Imaging. Chem. Soc. Rev. 2010, 39, 3031– 3056, DOI: 10.1039/b926512k[Crossref], [PubMed], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXptFygs7c%253D&md5=44314b2f8c76d4da56b63ceb1dc3a60aDelivering quantum dots to cells: bioconjugated quantum dots for targeted and nonspecific extracellular and intracellular imagingBiju, Vasudevanpillai; Itoh, Tamitake; Ishikawa, MitsuruChemical Society Reviews (2010), 39 (8), 3031-3056CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Bioconjugated nanomaterials offer endless opportunities to advance both nanobiotechnol. and biomedical technol. In this regard, semiconductor nanoparticles, also called quantum dots, are of particular interest for multimodal, multifunctional and multiplexed imaging of biomols., cells, tissues and animals. The unique optical properties, such as size-dependent tunable absorption and emission in the visible and NIR regions, narrow emission and broad absorption bands, high photoluminescence quantum yields, large one- and multi-photon absorption cross-sections, and exceptional photostability are the advantages of quantum dots. Multimodal imaging probes are developed by interfacing the unique optical properties of quantum dots with magnetic or radioactive materials. Besides, cryst. structure of quantum dots adds scope for high-contrast x-ray and TEM imaging. Yet another unique feature of a quantum dot is its spacious and flexible surface which is promising to integrate multiple ligands and antibodies and construct multi-functional probes for bioimaging. In this crit. review, the authors will summarize recent advancements in the prepn. of biocompatible quantum dots, bioconjugation of quantum dots, and applications of quantum dots and their bioconjugates for targeted and nonspecific imaging of extracellular and intracellular proteins, organelles and functions (181 refs.).129Viana, O. S.; Ribeiro, M. S.; Fontes, A.; Santos, B. S. Quantum Dots in Photodynamic Therapy. In Oxidative Stress in Applied Basic Research and Clinical Practice; Springer International Publishing: Switzerland, 2016; pp 525– 539.130Din, F. U.; Aman, W.; Ullah, I.; Qureshi, O. S.; Mustapha, O.; Shafique, S.; Zeb, A. Effective Use of Nanocarriers as Drug Delivery Systems for the Treatment of Selected Tumors. Int. J. Nanomed. 2017, 12, 7291– 7309, DOI: 10.2147/IJN.S146315[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7hslOjtQ%253D%253D&md5=db75f3b773624ea769aedb9b65997be8Effective use of nanocarriers as drug delivery systems for the treatment of selected tumorsDin Fakhar Ud; Aman Waqar; Ullah Izhar; Qureshi Omer Salman; Mustapha Omer; Shafique Shumaila; Zeb AlamInternational journal of nanomedicine (2017), 12 (), 7291-7309 ISSN:.Nanotechnology has recently gained increased attention for its capability to effectively diagnose and treat various tumors. Nanocarriers have been used to circumvent the problems associated with conventional antitumor drug delivery systems, including their nonspecificity, severe side effects, burst release and damaging the normal cells. Nanocarriers improve the bioavailability and therapeutic efficiency of antitumor drugs, while providing preferential accumulation at the target site. A number of nanocarriers have been developed; however, only a few of them are clinically approved for the delivery of antitumor drugs for their intended actions at the targeted sites. The present review is divided into three main parts: first part presents introduction of various nanocarriers and their relevance in the delivery of anticancer drugs, second part encompasses targeting mechanisms and surface functionalization on nanocarriers and third part covers the description of selected tumors, including breast, lungs, colorectal and pancreatic tumors, and applications of relative nanocarriers in these tumors. This review increases the understanding of tumor treatment with the promising use of nanotechnology.131Lombardo, D.; Kiselev, M. A.; Caccamo, M. T. Smart Nanoparticles for Drug Delivery Application: Development of Versatile Nanocarrier Platforms in Biotechnology and Nanomedicine. J. Nanomater. 2019, 2019, 1, DOI: 10.1155/2019/3702518132Singh, R.; Lillard, J. W. Nanoparticle-Based Targeted Drug Delivery. Exp. Mol. Pathol. 2009, 86, 215– 223, DOI: 10.1016/j.yexmp.2008.12.004[Crossref], [PubMed], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlslWhtrs%253D&md5=51bbe150de7e5f9db5c27a9717198dffNanoparticle-based targeted drug deliverySingh, Rajesh; Lillard, James W.Experimental and Molecular Pathology (2009), 86 (3), 215-223CODEN: EXMPA6; ISSN:0014-4800. (Elsevier B.V.)A review. Nanotechnol. could be defined as the technol. that has allowed for the control, manipulation, study, and manuf. of structures and devices in the "nanometer" size range. These nano-sized objects, e.g., "nanoparticles", take on novel properties and functions that differ markedly from those seen from items made of identical materials. The small size, customized surface, improved soly., and multi-functionality of nanoparticles will continue to open many doors and create new biomedical applications. Indeed, the novel properties of nanoparticles offer the ability to interact with complex cellular functions in new ways. This rapidly growing field requires cross-disciplinary research and provides opportunities to design and develop multifunctional devices that can target, diagnose, and treat devastating diseases such as cancer. This article presents an overview of nanotechnol. for the biologist and discusses the attributes of the authors' novel XPclad nanoparticle formulation that has shown efficacy in treating solid tumors, single dose vaccination, and oral delivery of therapeutic proteins.133Gupta, A.; Avci, P.; Sadasivam, M.; Chandran, R.; Parizotto, N.; Vecchio, D.; de Melo, W. C. M. A.; Dai, T.; Chiang, L. Y.; Hamblin, M. R. Shining Light on Nanotechnology to Help Repair and Regeneration. Biotechnol. Adv. 2013, 31, 607– 631, DOI: 10.1016/j.biotechadv.2012.08.003[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlWks73P&md5=39dc02860a75e67d45008d22b4e3d4c5Shining light on nanotechnology to help repair and regenerationGupta, Asheesh; Avci, Pinar; Sadasivam, Magesh; Chandran, Rakkiyappan; Parizotto, Nivaldo; Vecchio, Daniela; de Melo, Wanessa C. M. A.; Dai, Tianhong; Chiang, Long Y.; Hamblin, Michael R.Biotechnology Advances (2013), 31 (5), 607-631CODEN: BIADDD; ISSN:0734-9750. (Elsevier)A review. Phototherapy can be used in two completely different but complementary therapeutic applications. While low level laser (or light) therapy (LLLT) uses red or near-IR light alone to reduce inflammation, pain and stimulate tissue repair and regeneration, photodynamic therapy (PDT) uses the combination of light plus non-toxic dyes (called photosensitizers) to produce reactive oxygen species that can kill infectious microorganisms and cancer cells or destroy unwanted tissue (neo-vascularization in the choroid, atherosclerotic plaques in the arteries). The recent development of nanotechnol. applied to medicine (nanomedicine) has opened a new front of advancement in the field of phototherapy and has provided hope for the development of nanoscale drug delivery platforms for effective killing of pathol. cells and to promote repair and regeneration. Despite the well-known beneficial effects of phototherapy and nanomaterials in producing the killing of unwanted cells and promoting repair and regeneration, there are few reports that combine all three elements i.e. phototherapy, nanotechnol. and, tissue repair and regeneration. However, these areas in all possible binary combinations have been addressed by many workers. The present review aims at highlighting the combined multi-model applications of phototherapy, nanotechnol. and, reparative and regeneration medicine and outlines current strategies, future applications and limitations of nanoscale-assisted phototherapy for the management of cancers, microbial infections and other diseases, and to promote tissue repair and regeneration.134Bechet, D.; Couleaud, P.; Frochot, C.; Viriot, M. L.; Guillemin, F.; Barberi-Heyob, M. Nanoparticles as Vehicles for Delivery of Photodynamic Therapy Agents. Trends Biotechnol. 2008, 26, 612– 621, DOI: 10.1016/j.tibtech.2008.07.007[Crossref], [PubMed], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht12lsLjO&md5=ae637c2360d6699269aa6e14b0250c2aNanoparticles as vehicles for delivery of photodynamic therapy agentsBechet, Denise; Couleaud, Pierre; Frochot, Celine; Viriot, Marie-Laure; Guillemin, Francois; Barberi-Heyob, MurielTrends in Biotechnology (2008), 26 (11), 612-621CODEN: TRBIDM; ISSN:0167-7799. (Elsevier B.V.)A review. Photodynamic therapy (PDT) in cancer treatment involves the uptake of a photosensitizer by cancer tissue followed by photoirradn. The use of nanoparticles as carriers of photosensitizers is a very promising approach because these nanomaterials can satisfy all the requirements for an ideal PDT agent. This review describes and compares the different individual types of nanoparticles that are currently in use for PDT applications. Recent advances in the use of nanoparticles, including inorg. oxide-, metallic-, ceramic-, and biodegradable polymer-based nanomaterials as carriers of photosensitizing agents, are highlighted. The authors describe the nanoparticles in terms of stability, photocytotoxic efficiency, biodistribution and therapeutic efficiency. Finally, the authors summarize exciting new results concerning the improvement of the photophys. properties of nanoparticles by biphotonic absorption and upconversion.135Huang, P.; Li, Z.; Lin, J.; Yang, D.; Gao, G.; Xu, C.; Bao, L.; Zhang, C.; Wang, K.; Song, H. Photosensitizer-Conjugated Magnetic Nanoparticles for in Vivo Simultaneous Magnetofluorescent Imaging and Targeting Therapy. Biomaterials 2011, 32, 3447– 3458, DOI: 10.1016/j.biomaterials.2011.01.032[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisVKju74%253D&md5=6afb60b36ad1413ebc2406114e8a22acPhotosensitizer-conjugated magnetic nanoparticles for in vivo simultaneous magnetofluorescent imaging and targeting therapyHuang, Peng; Li, Zhiming; Lin, Jing; Yang, Dapeng; Gao, Guo; Xu, Cheng; Bao, Le; Zhang, Chunlei; Wang, Kan; Song, Hua; Hu, Hengyao; Cui, DaxiangBiomaterials (2011), 32 (13), 3447-3458CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)A major challenge in nanotechnol. and nanomedicine is to integrate tumor targeting, imaging, and selective therapy functions into a small single nanoparticle (< 50 nm). Herein, photosensitizer-conjugated magnetic nanoparticles with ∼20 nm in diam. were strategically designed and prepd. for gastric cancer imaging and therapy. The second generation photosensitizer chlorin e6 (Ce6) was covalently anchored on the surface of magnetic nanoparticles with silane coupling agent. We found that the covalently incorporated Ce6 mols. retained their spectroscopic and functional properties for near-IR (NIR) fluorescence imaging and photodynamic therapy (PDT), and the core magnetic nanoparticles offered the functions of magnetically guided drug delivery and magnetic resonance imaging (MRI). The as-prepd. single particle platform is suitable for simultaneous targeting PDT and in vivo dual-mode NIR fluorescence imaging and MRI of nude mice loaded with gastric cancer or other tumors.136Sun, Y.; Chen, Z. L.; Yang, X. X.; Huang, P.; Zhou, X. P.; Du, X. X. Magnetic Chitosan Nanoparticles as a Drug Delivery System for Targeting Photodynamic Therapy. Nanotechnology 2009, 20, 135102, DOI: 10.1088/0957-4484/20/13/135102[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlvF2qs78%253D&md5=c49cbca7e36253a9a86faec7b0d095a6Magnetic chitosan nanoparticles as a drug delivery system for targeting photodynamic therapySun, Yun; Chen, Zhi-long; Yang, Xiao-xia; Huang, Peng; Zhou, Xin-ping; Du, Xiao-xiaNanotechnology (2009), 20 (13), 135102/1-135102/8CODEN: NNOTER; ISSN:0957-4484. (Institute of Physics Publishing)Photodynamic therapy (PDT) has become an increasingly recognized alternative to cancer treatment in clinic. However, PDT therapy agents, namely photosensitizer (PS), are limited in application as a result of prolonged cutaneous photosensitivity, poor water soly. and inadequate selectivity, which are encountered by numerous chem. therapies. Magnetic chitosan nanoparticles provide excellent biocompatibility, biodegradability, non-toxicity and water soly. without compromising their magnetic targeting. Nevertheless, no previous attempt has been reported to develop an in vivo magnetic drug delivery system with chitosan nanoparticles for magnetic resonance imaging (MRI) monitored targeting photodynamic therapy. In this study, magnetic targeting chitosan nanoparticles (MTCNPs) were prepd. and tailored as a drug delivery system and imaging agents for PS, designated as PHPP. Results showed that PHPP-MTCNPs could be used in MRI monitored targeting PDT with excellent targeting and imaging ability. Non-toxicity and high photodynamic efficacy on SW480 carcinoma cells both in vitro and in vivo were achieved with this method at the level of 0-100 μM. Notably, localization of nanoparticles in skin and hepatic tissue was significantly less than in tumor tissue, therefore photosensitivity and hepatotoxicity can be attenuated.137Wang, S.; Gao, R.; Zhou, F.; Selke, M. Nanomaterials and Singlet Oxygen Photosensitizers: Potential Applications in Photodynamic Therapy. J. Mater. Chem. 2004, 14, 487– 493, DOI: 10.1039/b311429e[Crossref], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtlWms7c%253D&md5=2a4edccceafc7adf2afd1c47995f4cf8Nanomaterials and singlet oxygen photosensitizers: potential applications in photodynamic therapyWang, Shizhong; Gao, Ruomei; Zhou, Feimeng; Selke, MatthiasJournal of Materials Chemistry (2004), 14 (4), 487-493CODEN: JMACEP; ISSN:0959-9428. (Royal Society of Chemistry)In this review, we address a highly interdisciplinary field: the use of nanomaterials as carriers for singlet oxygen photosensitizers and their potential applications in photodynamic therapy. In particular, recent advances in the use of nanoparticles including inorg. oxide-, metallic-, and polymer-based nanocomposites as photosensitizer carriers are highlighted. We review advantages and shortcomings of these diverse approaches as far as their application for photodynamic therapy is concerned. Fullerenes and their derivs. are also included, focusing on recent studies on their structure, properties, and ability to generate singlet oxygen.138Huang, P.; Xu, C.; Lin, J.; Wang, C.; Wang, X.; Zhang, C.; Zhou, X.; Guo, S.; Cui, D. Folic Acid-Conjugated Graphene Oxide Loaded With Photosensitizers for Targeting Photodynamic Therapy. Theranostics 2011, 1, 2240– 250, DOI: 10.7150/thno/v01p0240139Tomao, S. Albumin-Bound Formulation of Paclitaxel (Abraxane Abi-007) in the Treatment of Breast Cancer. Int. J. Nanomed. 2009, 4, 99– 105, DOI: 10.2147/IJN.S3061[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVKjsrrM&md5=5f8b9ded87114b3dc3811851e0d6047eAlbumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancerMiele, Evelina; Spinelli, Gian Paolo; Miele, Ermanno; Tomao, Federica; Tomao, SilverioInternational Journal of Nanomedicine (2009), 4 (), 99-105CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press (NZ) Ltd.)A review. Breast cancer is the most common type of malignancy diagnosed in women. In the metastatic setting this disease is still uncurable. Taxanes represent an important class of antitumor agents which have proven to be fundamental in the treatment of advanced and early-stage breast cancer, but the clin. advances of taxanes have been limited by their highly hydrophobic mol. status. To overcome this poor water soly., lipid-based solvents have been used as a vehicle, and new systemic formulations have been developed, mostly for paclitaxel, which are Cremophor-free and increase the circulation time of the drug. ABI-007 is a novel, albumin-bound, 130-nm particle formulation of paclitaxel, free from any kind of solvent. It has been demonstrated to be superior to an equitoxic dose of std. paclitaxel with a significantly lower incidence of toxicities in a large, international, randomized phase III trial. The availability of new drugs, such as Abraxane, in assocn. with other traditional and non-traditional drugs (new antineoplastic agents and targeted mols.), will give the oncologist many different effective treatment options for patients in this setting.140Malam, Y.; Loizidou, M.; Seifalian, A. M. Liposomes and Nanoparticles: Nanosized Vehicles for Drug Delivery in Cancer. Trends Pharmacol. Sci. 2009, 30, 592– 599, DOI: 10.1016/j.tips.2009.08.004[Crossref], [PubMed], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlCku7zI&md5=6fea99b7e1736f29608d4b02b80a841eLiposomes and nanoparticles: nanosized vehicles for drug delivery in cancerMalam, Yogeshkumar; Loizidou, Marilena; Seifalian, Alexander M.Trends in Pharmacological Sciences (2009), 30 (11), 592-599CODEN: TPHSDY; ISSN:0165-6147. (Elsevier B.V.)A review. Nanoscale drug delivery systems using liposomes and nanoparticles are emerging technologies for the rational delivery of chemotherapeutic drugs in the treatment of cancer. Their use offers improved pharmacokinetic properties, controlled and sustained release of drugs and, more importantly, lower systemic toxicity. The com. availability of liposomal Doxil and albumin-nanoparticle-based Abraxane has focused attention on this innovative and exciting field. Recent advances in liposome technol. offer better treatment of multidrug-resistant cancers and lower cardiotoxicity. Nanoparticles offer increased precision in chemotherapeutic targeting of prostate cancer and new avenues for the treatment of breast cancer. Here we review current knowledge on the two technologies and their potential applications to cancer treatment.141Wilson, B. C.; Olivo, M.; Singh, G. Subcellular Localization of Photofrin and Aminolevulinic Acid and Photodynamic Cross-Resistance in Vitro in Radiation-Induced Fibrosarcoma Cells Sensitive or Resistant to Photofrin-Mediated Photodynamic Therapy. Photochem. Photobiol. 1997, 65, 166– 176, DOI: 10.1111/j.1751-1097.1997.tb01894.x[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlslansg%253D%253D&md5=1d5f1bc5f7554a7aafbb7b56101d15c9Subcellular localization of Photofrin and aminolevulinic acid and photodynamic cross-resistance in vitro in radiation-induced fibrosarcoma cells sensitive or resistant to Photofrin-mediated photodynamic therapyWilson, B. C.; Olivo, M.; Singh, G.Photochemistry and Photobiology (1997), 65 (1), 166-176CODEN: PHCBAP; ISSN:0031-8655. (American Society for Photobiology)The subcellular and, specifically, mitochondrial localization of the photodynamic sensitizers Photofrin and aminolevulinic acid (ALA)-induced protoporphyrin-IX (PpIX) has been investigated in vitro in radiation-induced fibrosarcoma (RIF) tumor cells. Comparisons were made of parental RIF-1 cells and cells (RIF-8A) in which resistance to Photofrin-mediated photodynamic therapy (PDT) has been induced. The effect on the uptake kinetics of Photofrin of coincubation with one of the mitochondria-specific probes 10N-Nonyl acridine orange (NAO) or rhodamine-123 (Rh-123) and vice versa was examd. The subcellular colocalization of Photofrin and PpIX with Rh-123 was detd. by double-label confocal fluorescence microscopy. Clonogenic cell survival after ALA-mediated PDT was detd. in RIF-1 and RIF-8A cells to investigate cross-resistance with Photofrin-mediated PDT. At long (18 h) Photofrin incubation times, stronger colocalization of Photofrin and Rh-123 was seen in RIF-1 than in RIF-8A cells. Differences between RIF-1 and RIF-8A in the competitive mitochondrial binding of NAO or Rh-123 with Photofrin suggest that the inner mitochondrial membrane is a significant Photofrin binding site. The differences in this binding may account for the PDT resistance in RIF-8A cells. With ALA, the peak accumulations of PpIX occurred at 5 h for both cells, and followed a diffuse cytoplasmic distribution compared to mitochondrial localization at 1 h ALA incubation. There was rapid efflux of PpIX from both RIF-1 and RIF-8A. As with Photofrin, ALA-induced PpIX exhibited weaker mitochondrial localization in RIF-8A than in RIF-1 cells. Clonogenic survival demonstrated cross-resistance to incubation in PpIX but not to ALA-induced PpIX, implying differences in mitochondrial localization and/or binding, depending on the source of the PpIX within the cells.142Celli, J. P.; Solban, N.; Liang, A.; Pereira, S. P.; Hasan, T. Verteporfin-Based Photodynamic Therapy Overcomes Gemcitabine Insensitivity in a Panel of Pancreatic Cancer Cell Lines. Lasers Surg. Med. 2011, 43, 565– 574, DOI: 10.1002/lsm.21093[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MbmvFOjsQ%253D%253D&md5=288f096f6bfcc64aefee1de9c1bddad8Verteporfin-based photodynamic therapy overcomes gemcitabine insensitivity in a panel of pancreatic cancer cell linesCelli Jonathan P; Solban Nicolas; Liang Alvin; Pereira Stephen P; Hasan TayyabaLasers in surgery and medicine (2011), 43 (7), 565-74 ISSN:.BACKGROUND AND OBJECTIVE: Pancreatic cancer is notoriously difficult to treat and resistant to virtually all therapeutics including gemcitabine, the standard front line agent for palliative chemotherapy. Early clinical studies point to a potential role for photodynamic therapy (PDT) in the management of this deadly disease. Here we examine PDT with verteporfin for treatment of cells that are nonresponsive to gemcitabine and identify intracellular and extracellular factors that govern sensitivity to each modality. STUDY DESIGN: Using MTS we assess cytotoxicity of verteporfin-PDT in gemcitabine-treated nonresponsive populations from a panel of five pancreatic cancer cell lines representing a range of tumor histopathology and origin. We conduct Western blots for pro-/anti-apoptotic proteins bax and Bcl-XL to identify factors relevant to PDT and gemcitabine sensitivity. To examine the role of extracellular matrix influences we compare response to each modality in traditional cell culture conditions and cells grown on a laminin-rich basement membrane. RESULTS: All cell lines have gemcitabine nonresponsive populations (17-33%) at doses up to 1 mM while moderate total verteporfin PDT doses (1-6 μM J/cm2) produce nearly complete killing. Our data shows that cells that are nonresponsive to sustained gemcitabine incubation are sensitive to verteporfin PDT indicating that the latter is agnostic to gemcitabine sensitivity. Verteporfin-based PDT decreases Bcl-XL and increases the bax/Bcl-XL ratio toward a pro-apoptotic balance. Insensitivity to gemcitabine is increased in cells that are adherent to basement membrane relative to traditional tissue culture conditions. CONCLUSIONS: Collectively these results indicate the ability of verteporfin-based PDT to bypass intracellular and extracellular cues leading to gemcitabine resistance and point to the emerging role of this therapy for treatment of pancreatic cancer.143Mahalingam, S. M.; Ordaz, J. D.; Low, P. S. Targeting of a Photosensitizer to the Mitochondrion Enhances the Potency of Photodynamic Therapy. ACS Omega 2018, 3, 6066– 6074, DOI: 10.1021/acsomega.8b00692[ACS Full Text], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVKmsrzM&md5=2c1106ef23c23ca06e6fe7e3f3bee18aTargeting of a Photosensitizer to the Mitochondrion Enhances the Potency of Photodynamic TherapyMahalingam, Sakkarapalayam M.; Ordaz, Josue D.; Low, Philip S.ACS Omega (2018), 3 (6), 6066-6074CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)Photodynamic therapy (PDT) involves use of a photosensitizer, whose activation with light leads to the prodn. of singlet oxygen (SOS), generation of reactive oxygen species (ROS), and initiation of assocd. cell toxicity. Because a cell's mitochondria constitute sites where oxygen levels are high, ROS can be readily produced, and apoptosis is commonly initiated. Therefore, an ideal PDT agent might be a potent photosensitizer that could naturally accumulate in mitochondria. Although a no. of mitochondria-targeting moieties, including triphenylphosphine, guanidinium, and bisguanidium, have been identified, a quant. comparison of their efficacies in targeting mitochondria has not been performed. In this study, we have prepd. triphenylphosphine, guanidinium, and bisguanidium derivs. of the FDA-approved PDT agent verteporfin (Visudyne, benzoporphyrin deriv.-monoacid ring A: BPD-MA) and compared their abilities to induce the intracellular perturbations common to potent PDT agents. Cellular parameters examd. included subcellular localization of the verteporfin, real-time monitoring of SOS prodn., quantitation of reactive oxygen species (ROS) generation, anal. of mitochondria and chromatin integrity, characterization of cytoskeletal disruption and evaluation of cytochrome C release as a measure of apoptosis. An anal. of these parameters demonstrates that the triphenylphosphine deriv. (0323) has better mitochondria-targeting efficacy, SOS prodn., and mitochondria membrane toxicity than either unmodified verteporfin or its guanidinium derivs. Consistent with this potency, 0323 also induced the most prominent mitochondria swelling, actin depolymn., pyknosis, and cytochrome C release. We conclude that triphenylphosphine has a better mitochondria-targeting moiety than guanidinium or bis-guanidinium and those PDT photosensitizers with improved cytotoxicities can be prepd. by conjugating a mitochondria-targeting moiety to the desired photosensitizer.144Zielonka, J.; Joseph, J.; Sikora, A.; Hardy, M.; Ouari, O.; Vasquez-Vivar, J.; Cheng, G.; Lopez, M.; Kalyanaraman, B. Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications. Chem. Rev. 2017, 117, 10043– 10120, DOI: 10.1021/acs.chemrev.7b00042[ACS Full Text], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVGrs7fJ&md5=53093198d06913e216b0614a8c7ff579Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic ApplicationsZielonka, Jacek; Joseph, Joy; Sikora, Adam; Hardy, Micael; Ouari, Olivier; Vasquez-Vivar, Jeannette; Cheng, Gang; Lopez, Marcos; Kalyanaraman, BalaramanChemical Reviews (Washington, DC, United States) (2017), 117 (15), 10043-10120CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurol. diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small mols. Depending on the approach used, and the potentials of cell and mitochondrial membranes, more than 1000-fold higher mitochondrial concn. can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiol. and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this review, the authors discuss efforts to target small-mol. compds. to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. The authors describe the physicochem. basis for mitochondrial accumulation of lipophilic cations, synthetic chem. strategies to target compds. to mitochondria, mitochondrial probes and sensors, and examples of mitochondrial targeting of bioactive compds. Finally, the authors review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.145Wang, H.; Gao, Z.; Liu, X.; Agarwal, P.; Zhao, S.; Conroy, D. W.; Ji, G.; Yu, J.; Jaroniec, C. P.; Liu, Z.; Lu, X.; Li, X.; He, X. Targeted Production of Reactive Oxygen Species in Mitochondria to Overcome Cancer Drug Resistance. Nat. Commun. 2018, 9, 1– 16, DOI: 10.1038/s41467-018-02915-8[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1KrsrzP&md5=04efe962f0f7b082499e401485f02930Phase and structure engineering of copper tin heterostructures for efficient electrochemical carbon dioxide reductionWang, Pengtang; Qiao, Man; Shao, Qi; Pi, Yecan; Zhu, Xing; Li, Yafei; Huang, XiaoqingNature Communications (2018), 9 (1), 1-10CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)While engineering the phase and structure of electrocatalysts could regulate the performance of many typical electrochem. processes, its importance to the carbon dioxide electroredn. has been largely unexplored. Herein, a series of phase and structure engineered copper-tin dioxide catalysts have been created and thoroughly exploited for the carbon dioxide electroredn. to correlate performance with their unique structures and phases. The copper oxide/hollow tin dioxide heterostructure catalyst exhibits promising performance, which can tune the products from carbon monoxide to formic acid at high faradaic efficiency by simply changing the electrolysis potentials from -0.7 VRHE to -1.0 VRHE. The excellent performance is attributed to the abundant copper/tin dioxide interfaces involved in the copper oxide/hollow tin dioxide heterostructure during the electrochem. process, decreasing the reaction free-energies for the formation of COOH* species. Our work reported herein emphasizes the importance of phase and structure modulating of catalysts for enhancing electrochem. CO2 redn. and beyond.146Zhao, X.; Huang, Y.; Yuan, G.; Zuo, K.; Huang, Y.; Chen, J.; Li, J.; Xue, J. A Novel Tumor and Mitochondria Dual-Targeted Photosensitizer Showing Ultra-Efficient Photodynamic Anticancer Activities. Chem. Commun. 2019, 55, 866– 869, DOI: 10.1039/C8CC09456J[Crossref], [PubMed], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFCksLnL&md5=b2ebbf3e3e6a8c1c921d8006fe912242A novel tumor and mitochondria dual-targeted photosensitizer showing ultra-efficient photodynamic anticancer activitiesZhao, Xuan; Huang, Yuchao; Yuan, Gankun; Zuo, Ke; Huang, Yafan; Chen, Juanjuan; Li, Jinyu; Xue, JinpingChemical Communications (Cambridge, United Kingdom) (2019), 55 (6), 866-869CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)We designed and synthesized a simple, but highly effective photosensitizer (G-Mito-Pc), which can precisely target the mitochondria of epidermal growth factor receptor (EGFR)-overexpressing cancer cells, to achieve dual targeting function at both cell and organelle levels in cancer therapy. We further explored the possible mol. mechanism of the enhanced bioactivity of G-Mito-Pc compared to that of the ref. photosensitizer using mol. dynamics simulations on their interactions with a physiol. relevant mitochondrial membrane model.147Sibrian-Vazquez, M.; Nesterova, I. V.; Jensen, T. J.; Vicente, M. G. H. Mitochondria Targeting by Guanidine- and Biguanidine-Porphyrin Photosensitizers. Bioconjugate Chem. 2008, 19, 705– 713, DOI: 10.1021/bc700393u[ACS Full Text], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhvVGgu7g%253D&md5=773afe6be2634fd0174f9593a56923c0Mitochondria Targeting by Guanidine- and Biguanidine-Porphyrin PhotosensitizersSibrian-Vazquez, Martha; Nesterova, Irina V.; Jensen, Timothy J.; Vicente, M. Graca H.Bioconjugate Chemistry (2008), 19 (3), 705-713CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)We report the syntheses of three new amphiphilic porphyrin derivs., contg. a guanidine, a biguanidine, or an MLS peptide, that were designed to target the cell mitochondria. The guanidine- and biguanidine-porphyrins are poorly sol. in water, forming J-type aggregates in aq. solns. On the other hand, the porphyrin-MLS peptide conjugate bearing a low mol. wt. PEG spacer is highly water-sol. and does not aggregate in aq. media. The fluorescence quantum yields detd. for all porphyrins were higher at low pH (<6) and the porphyrin-peptide conjugate had the highest quantum yields in aq. media. All porphyrins showed low dark toxicity toward human carcinoma HEp2 cells, and the guanidine-porphyrin was the most phototoxic (IC50 = 4.8 μM at 1 J cm-2), followed by the biguanidine-porphyrin and the porphyrin-MLS (IC50 = 8.2 μM and 9.8 μM at 1 J cm-2, resp.). The porphyrin-MLS peptide conjugate accumulated the most within cells of all porphyrins at all times investigated and the biguanidine-porphyrin accumulated the least. Both the guanidine- and biguanidine-porphyrins localized within cell mitochondria and, in addn., were found in the lysosomes and the ER (in the case of the guanidine-porphyrin). In contrast, the porphyrin-MLS peptide conjugate localized mainly within the cell lysosomes.148Canal, F.; Vicent, M. J.; Pasut, G.; Schiavon, O. Relevance of Folic Acid/Polymer Ratio in Targeted PEG-Epirubicin Conjugates. J. Controlled Release 2010, 146, 388– 399, DOI: 10.1016/j.jconrel.2010.05.027[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFWgt7vF&md5=7ed2bb3bc3bb6a29d3bfabcac7bc8422Relevance of folic acid/polymer ratio in targeted PEG-epirubicin conjugatesCanal, Fabiana; Vicent, Maria J.; Pasut, Gianfranco; Schiavon, OddoneJournal of Controlled Release (2010), 146 (3), 388-399CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)A series of PEG-epirubicin conjugates with different folic acid contents per polymer chain was synthesized in order to study the influence of polymer/targeting moiety ratio on selective cytotoxicity, cellular uptake and intracellular localization. Analogous carboxyl-terminated conjugates without folic acid were studied as control. The heterobifunctional HO-PEG-COOH was used as polymeric carrier, allowing the synthesis of conjugates with a good control over the chem. structure and the drug/polymer and polymer/targeting residue ratios. A dendron structure was synthesized at one end of the PEG chain with the aim to increase the no. of folic acid mols. L-2-aminoadipic acid was used as branching unit. The conjugates showed high stability under several physiol. conditions. Biol. evaluation was carried out in A549, HeLa and KB-3-1 human cell lines, as these cells have different levels of folate receptor (FR) expression. In particular A549 cells are FR neg. (FR-), HeLa cells are FR pos. (FR+) and KB-3-1 cells over-express FR (FR++). It was clearly shown that the biol. activity of the conjugates was influenced by the presence and the no. of folic acid mols. per polymer chain and by the level of FR expression on cell surface. Conjugates conformation in soln. was also studied, as differences in size might well affect cell internalization. In the cell viability assay, conjugates without folic acid were unexpectedly more cytotoxic than the targeted conjugates, but their IC50 values were similar in the three cell lines. Differently, the anti-proliferative activity of targeted derivs. markedly increased going from FR(-) to FR(++) cells. FACS and confocal microscopy studies showed greater cellular internalization with the targeted conjugates than with their non-targeted analogs; more importantly, this relationship is clearly dependent on folic acid content in the conjugates and FR expression level in the cell line used.149Farokhzad, O. C.; Langer, R. Impact of Nanotechnology on Drug Delivery. ACS Nano 2009, 3, 16– 20, DOI: 10.1021/nn900002m[ACS Full Text], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnvFGisQ%253D%253D&md5=092946aed00c4a9f740df6505b2e805cImpact of Nanotechnology on Drug DeliveryFarokhzad, Omid C.; Langer, RobertACS Nano (2009), 3 (1), 16-20CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)A review. Nanotechnol. is the engineering and manufg. of materials at the at. and mol. scale. In its strictest definition from the National Nanotechnol. Initiative, nanotechnol. refers to structures roughly in the 1-100 nm size regime in at least one dimension. Despite this size restriction, nanotechnol. commonly refers to structures that are up to several hundred nanometers in size and that are developed by top-down or bottom-up engineering of individual components. Herein, we focus on the application of nanotechnol. to drug delivery and highlight several areas of opportunity where current and emerging nanotechnologies could enable entirely novel classes of therapeutics.150Lin, L.; Xiong, L.; Wen, Y.; Lei, S.; Deng, X.; Liu, Z.; Chen, W.; Miao, X. Active Targeting of Nano-Photosensitizer Delivery Systems for Photodynamic Therapy of Cancer Stem Cells. J. Biomed. Nanotechnol. 2015, 11, 531– 554, DOI: 10.1166/jbn.2015.2090[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlt1Ggtrk%253D&md5=69cbcdd4b863a3e3a4c53a60835d3594Active targeting of nano-photosensitizer delivery systems for photodynamic therapy of cancer stem cellsLin, Liangwu; Xiong, Li; Wen, Yu; Lei, Sanlin; Deng, Xiaofeng; Liu, Zhipeng; Chen, Wei; Miao, XiongyingJournal of Biomedical Nanotechnology (2015), 11 (4), 531-554CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)A review. Cancer stem cells are believed to be the basis for tumor initiation, development, metastasis and recurrence; are resistant to most traditional therapies (e.g., chemotherapy and radiotherapy); and have the ability to self-renew, proliferate and differentiate. Photodynamic therapy may be a promising novel treatment for drug-resistant cancer stem cells because of the selectivity of the photosensitizer. One of the most important issues to overcome in photodynamic therapy is the photosensitizer-targeted delivery to tumor cells, esp. cancer stem cells. Nano-photosensitizers comprising mol. photosensitizers and water-dispersible nanocarriers with or without moieties possessing the ability for specific binding to cancer cells or cancer stem cells are a promising strategy for active targeted photosensitizer delivery and photodynamic therapy-targeted therapy of tumors. In this review, we highlight current and future prospects for potential strategies based on nanoscience and nanotechnol. for nano-photosensitizer-targeted delivery in the photodynamic therapy treatment of cancer cells, esp. cancer stem cells.151Chen, L.; Miao, W.; Tang, X.; Zhang, H.; Wang, S.; Luo, F.; Yan, J. Inhibitory Effect of Neuropilin-1 Monoclonal Antibody (NRP-1 MAB) on Glioma Tumor in Mice. J. Biomed. Nanotechnol. 2013, 9, 551– 558, DOI: 10.1166/jbn.2013.1623[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXltlGqsrk%253D&md5=3787730e120f9b3fbc8c6a997ae20382Inhibitory effect of neuropilin-1 monoclonal antibody (NRP-1 MAb) on glioma tumor in miceChen, Lukui; Miao, Wei; Tang, Xiaoyong; Zhang, Haipeng; Wang, Shengyu; Luo, Fanghong; Yan, JianghuaJournal of Biomedical Nanotechnology (2013), 9 (4), 551-558CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)This article reports the effect of Neuropilin-1 monoclonal antibody (NRP-1 MAb) on glioma cell lines in vitro and the effect on nude mice bearing glioma tumor (U87) in vivo. MTT, the scratch test and transwell test were used to evaluate the inhibitory effect of NRP-1 MAb on glioma cell lines. The tissue distribution and tumor targeting capability of NRP-1 MAb in U87 Xenografts nude mice was detd. in Optical Imaging. Anti-glioma expt. was carried out by NRP-1 MAb on U87 Xenografts nude mice. NRP-1 MAb was showed to inhibit the proliferation, migration and invasion of glioma cells. NRP-1 MAb can specifically target the tumor in U87 Xenografts nude mice and reduce the proliferation activity of the tumor. The results of this study indicate that NRP-1 MAb can inhibit the proliferation, migration and metastasis of glioma cell lines and can target the glioma tumor to reduce tumor growth. Therefore, NRP-1 MAb may be an effective agent for glioma-targeted therapy.152Zhang, Z.; Sun, Q.; Zhong, J.; Yang, Q.; Li, H.; Cheng, D.; Liang, B.; Shuai, X. Magnetic Resonance Imaging-Visible and PH-Sensitive Polymeric Micelles for Tumor Targeted Drug Delivery. J. Biomed. Nanotechnol. 2014, 10, 216– 226, DOI: 10.1166/jbn.2014.1729[Crossref], [PubMed], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkvV2iu7w%253D&md5=2539e7dd35175465924a6fd90a571127Magnetic resonance imaging-visible and pH-sensitive polymeric micelles for tumor targeted drug deliveryZhang, Zuoquan; Sun, Qiquan; Zhong, Jinglian; Yang, Qihua; Li, Hao; Cheng, Du; Liang, Biling; Shuai, XintaoJournal of Biomedical Nanotechnology (2014), 10 (2), 216-226CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)Folate-functionalized copolymers of poly(ethylene glycol) and 2-(diisopropylamino) ethylamine grafted poly(L-aspartic acid) are synthesized. The copolymers can self-assemble into nanoscaled micelles encapsulated with hydrophobic model drug Fluorescein Diacetate (FDA) and MRI diagnostic agents superparamagnetic iron oxide nanoparticles (SPIONs) in aq. soln. of a neutral pH resembling physiol. environment, whereas disassemble in acidic endosomal/lysosomal compartments of tumor cells to achieve rapid drug release. In vitro drug release study showed that FDA release from the pH-sensitive micelles was much faster at pH 5.0 than at pH 7.4. Clustering of SPIONs inside the hydrophobic core of the micelles resulted in a high spin-spin (T2) relaxivity for a super MRI sensitivity. Cell culture studies showed that the FDA-SPION-loaded micelles were effectively internalized by human hepatic Bel-7402 cancer cells following a folate receptor-mediated targeting mechanism, and then FDA was rapidly release from micelles inside lysosomal compartments. Micelles encapsulating paclitaxel (PTX) studies showed it can induce more effective cell toxicity. This study demonstrated the great potential of the pH-sensitive micelles as an effective multifunctional nanomedician platform for cancer therapy due to their active tumor targeting, pH-triggered drug release and ultrasensitive MRI responsiveness.153Kim, K. S.; Kim, J.; Kim, D. H.; Hwang, H. S.; Na, K. Multifunctional Trastuzumab-Chlorin E6 Conjugate for the Treatment of HER2-Positive Human Breast Cancer. Biomater. Sci. 2018, 6, 1217– 1226, DOI: 10.1039/C7BM01084B[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXkt1Kgurk%253D&md5=133b9940dbb9a61a3fded1e27ca9ad66Multifunctional trastuzumab-chlorin e6 conjugate for the treatment of HER2-positive human breast cancerKim, Kyoung Sub; Kim, Jiyoung; Kim, Da Hye; Hwang, Hee Sook; Na, KunBiomaterials Science (2018), 6 (5), 1217-1226CODEN: BSICCH; ISSN:2047-4849. (Royal Society of Chemistry)Effective penetration and targeted delivery of anticancer drugs into tumor tissues are limiting factors for achieving enhanced therapeutic efficacy. In order to overcome the disadvantages of antibody therapy (limited penetration efficacy into tumor tissues) and photodynamic therapy (low targeting efficiency) on the treatment of HER2-pos. human breast cancer simultaneously, an antibody and photosensitizer combined Trastuzumab-chlorin e6 conjugate (TMPC) was synthesized. TMPC exhibits high singlet oxygen generation under laser irradn. In vitro data show that TMPC has specific HER2 selective interactions, and ROS generation ability upon laser irradn. induces significant cell death in HER2-pos. breast cancer cells. The enhanced tissue penetration ability and tissue access of TMPC resulting from local tissue destruction by ROS generated from Ce6 is also demonstrated in breast cancer tissue blocks. The enhanced ability of TMPC is supported by in vivo fluorescence images of SK-BR-3 (HER2-pos. cancer cells) tumor-bearing mice. The in vivo test demonstrates approx. 6-fold enhanced accumulation of TMPC in xenograft tumors with a longer retention time compared to that of the PEG-Ce6 conjugate at 24 h. Thus, trastuzumab and photosensitizer conjugation brings synergistic effects for HER2 selective targeting, where TMPC enhanced tumor tissue penetration improves tumor tissue access and responsiveness of trastuzumab in HER2 overexpressing breast cancer.154Mitri, Z.; Constantine, T.; O’Regan, R. The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy. Chemother. Res. Pract. 2012, 2012, 1– 7, DOI: 10.1155/2012/743193155Kim, J.; Jo, Y. um; Na, K. Photodynamic Therapy with Smart Nanomedicine. Arch. Pharmacal Res. 2020, 43, 22– 31, DOI: 10.1007/s12272-020-01214-5[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisleksbo%253D&md5=9f2dc55f9012722a782c303612f030f4Photodynamic therapy with smart nanomedicineKim, Jiyoung; Jo, Young-um; Na, KunArchives of Pharmacal Research (2020), 43 (1), 22-31CODEN: APHRDQ; ISSN:0253-6269. (Pharmaceutical Society of Korea)Abstr.: For several decades, clin. demands for utilization of photodynamic therapy (PDT) have been increasing. Notably, PDT was mainly applied for cancer therapy, and most photosensitizers (PSs) were developed to treat cancer. The advantages of PDT, such as minimal invasiveness and local treatment by topical light irradn., have made it possible to widen the range of target diseases. Thus, PDT has been clin. used for treatment of various diseases (e.g., cancer, acne, and age-related macular degeneration). However, PS, which is the main component of PDT, exhibits several shortcomings such as low soly., low bioavailability, and lack of lesion selectivity for use as a therapeutic agent. Therefore, many research projects have been performed to develop smart PS. To increase therapeutic efficacy and to decrease adverse effects in normal tissue at the same time, PS incorporation within nanoscaled delivery systems is evolving. This review provides a comprehensive explanation of PDT in smart nanomedicine, which is academically and clin. utilized in the treatment of various diseases.156Kessel, D. The Role of Low-Density Lipoprotein in the Biodistribution of Photosensitizing Agents. J. Photochem. Photobiol., B 1992, 14, 261– 262, DOI: 10.1016/1011-1344(92)85103-2[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3s%252FlvVWgtA%253D%253D&md5=c0f0f7b227d822c811d874f96aa6fba8The role of low-density lipoprotein in the biodistribution of photosensitizing agentsKessel DJournal of photochemistry and photobiology. B, Biology (1992), 14 (3), 261-2 ISSN:1011-1344.There is no expanded citation for this reference.157Sibani, S. A.; McCarron, P. A.; Woolfson, A. D.; Donnelly, R. F. Photosensitiser Delivery for Photodynamic Therapy. Part 2: Systemic Carrier Platforms. Expert Opin. Drug Delivery 2008, 5, 1241– 1254, DOI: 10.1517/17425240802444673[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlaisrfN&md5=d33451d4188ccdeb2101bf2083ce6642Photosensitiser delivery for photodynamic therapy. Part 2: systemic carrier platformsSibani, Stephane A.; McCarron, Paul A.; Woolfson, A. David; Donnelly, Ryan F.Expert Opinion on Drug Delivery (2008), 5 (11), 1241-1254CODEN: EODDAW; ISSN:1742-5247. (Informa Healthcare)A review. Background: The treatment of solid tumors and angiogenic ocular diseases by photodynamic therapy (PDT) requires the injection of a photosensitizer (PS) to destroy target cells through a combination of visible light irradn. and mol. oxygen. There is currently great interest in the development of efficient and specific carrier delivery platforms for systemic PDT. Objective: This article aims to review recent developments in systemic carrier delivery platforms for PDT, with an emphasis on target specificity. Methods: Recent publications, spanning the last five years, concerning delivery carrier platforms for systemic PDT were reviewed, including PS conjugates, dendrimers, micelles, liposomes and nanoparticles. Results/conclusion: PS conjugates and supramol. delivery platforms can improve PDT selectivity by exploiting cellular and physiol. specificities of the targeted tissue. Overexpression of receptors in cancer and angiogenic endothelial cells allows their targeting by affinity-based moieties for the selective uptake of PS conjugates and encapsulating delivery carriers, while the abnormal tumor neovascularisation induces a specific accumulation of heavy weighted PS carriers by enhanced permeability and retention (EPR) effect. In addn., polymeric prodrug delivery platforms triggered by the acidic nature of the tumor environment or the expression of proteases can be designed. Promising results obtained with recent systemic carrier platforms will, in due course, be translated into the clinic for highly efficient and selective PDT protocols.158Ke, M.-R.; Yeung, S.-L.; Ng, D. K. P.; Fong, W.-P.; Lo, P.-C. Preparation and In Vitro Photodynamic Activities of Folate-Conjugated Distyryl Boron Dipyrromethene Based Photosensitizers. J. Med. Chem. 2013, 56, 8475– 8483, DOI: 10.1021/jm4009168[ACS Full Text], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFKlu7jO&md5=6756371bb8d6718a4f46afe42cdab588Preparation and in Vitro Photodynamic Activities of Folate-Conjugated Distyryl Boron Dipyrromethene Based PhotosensitizersKe, Mei-Rong; Yeung, Sin-Lui; Ng, Dennis K. P.; Fong, Wing-Ping; Lo, Pui-ChiJournal of Medicinal Chemistry (2013), 56 (21), 8475-8483CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Two folate-conjugated diiododistyryl boron dipyrromethenes have been prepd. and characterized with various spectroscopic methods. These conjugates exhibit higher photocytotoxicity toward the KB human nasopharyngeal carcinoma cells, which have high expression of folate receptors when compared with the MCF-7 human breast adenocarcinoma cells, which have low expression of folate receptors. The difference in photocytotoxicity for these two cell lines is particularly large for the conjugate with a shorter oligoethylene glycol linker (compd. 11a) as a result of its higher cellular uptake and slightly lower aggregation tendency. Its IC50 value toward KB cells (0.06 μM) is 43-fold lower than that for MCF-7 cells, while the difference is only 6-fold for the analog with a longer linker (compd. 11b). The length of the spacer also affects their subcellular localization. While compd. 11a shows high affinity toward the endoplasmic reticulum of KB cells, conjugate 11b is mainly localized in the lysosomes.159Cheung, A.; Bax, H. J.; Josephs, D. H.; Ilieva, K. M.; Pellizzari, G.; Opzoomer, J.; Bloomfield, J.; Fittall, M.; Grigoriadis, A.; Figini, M.; Canevari, S.; Spicer, J. F.; Tutt, A. N.; Karagiannis, S. N. Targeting Folate Receptor Alpha for Cancer Treatment. Oncotarget 2016, 7, 52553– 52574, DOI: 10.18632/oncotarget.9651[Crossref], [PubMed], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s%252FlsVantA%253D%253D&md5=cac31bd8f8f082eca3ce9041770e4a23Targeting folate receptor alpha for cancer treatmentCheung Anthony; Bax Heather J; Josephs Debra H; Ilieva Kristina M; Pellizzari Giulia; Opzoomer James; Bloomfield Jacinta; Fittall Matthew; Karagiannis Sophia N; Cheung Anthony; Ilieva Kristina M; Fittall Matthew; Grigoriadis Anita; Tutt Andrew N; Karagiannis Sophia N; Bax Heather J; Josephs Debra H; Spicer James F; Figini Mariangela; Canevari SilvanaOncotarget (2016), 7 (32), 52553-52574 ISSN:.Promising targeted treatments and immunotherapy strategies in oncology and advancements in our understanding of molecular pathways that underpin cancer development have reignited interest in the tumor-associated antigen Folate Receptor alpha (FRα). FRα is a glycosylphosphatidylinositol (GPI)-anchored membrane protein. Its overexpression in tumors such as ovarian, breast and lung cancers, low and restricted distribution in normal tissues, alongside emerging insights into tumor-promoting functions and association of expression with patient prognosis, together render FRα an attractive therapeutic target. In this review, we summarize the role of FRα in cancer development, we consider FRα as a potential diagnostic and prognostic tool, and we discuss different targeted treatment approaches with a specific focus on monoclonal antibodies. Renewed attention to FRα may point to novel individualized treatment approaches to improve the clinical management of patient groups that do not adequately benefit from current conventional therapies.160Savellano, M. D.; Hasan, T. Photochemical Targeting of Epidermal Growth Factor Receptor: A Mechanistic Study. Clin. Cancer Res. 2005, 11, 1658– 1668, DOI: 10.1158/1078-0432.CCR-04-1902[Crossref], [PubMed], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhvVSrt7o%253D&md5=de8810d77e74a48274758152edcd5c68Photochemical Targeting of Epidermal Growth Factor Receptor: A Mechanistic StudySavellano, Mark D.; Hasan, TayyabaClinical Cancer Research (2005), 11 (4), 1658-1668CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)PURPOSE: Photoimmunotherapy may allow target-specific photodynamic destruction of malignancies and may also potentiate anticancer antibody therapies. However, clin. use of either of the two modalities is limited for different reasons. Antibody therapies suffer from being primarily cytostatic and the need for prolonged administration with consequent side effects. In the case of photoimmunotherapy, a major impediment has been the absence of well-characterized photosensitizer immunoconjugates (PIC). In this investigation, we suggest a strategy to overcome these limitations and present the successful targeting of epidermal growth factor receptor (EGFR) using a well-characterized PIC. Exptl. Design: The PIC consisted of the EGFR-recognizing chimeric monoclonal antibody, C225, conjugated with a two-branched polyethylene glycol and benzoporphyrin deriv. (BPD, Verteporfin). Mechanistic studies included photophysics, phototoxicity, cellular uptake, and catabolism expts. to yield dosimetric parameters. Target cells included two EGFR-overexpressing human cancer cell lines, OVCAR-5 and A-431. Nontarget cells included an EGFR-neg. fibroblast cell line, 3T3-NR6, and a monocyte-macrophage cell line, J774. RESULTS: BPD-C225 PICs targeted and photodynamically killed EGFR-overexpressing cells, whereas free BPD exhibited no specificity. On a per mol basis, PICs were less phototoxic than free BPD, but PICs were very selective for target cells, whereas free BPD was not. Phototoxicity of the PICs increased at prolonged incubations. Photodynamic dose calcns. indicated that PIC photophysics, photochem., catabolism, and subcellular localization were important determinants of PIC phototoxic potency. CONCLUSIONS: This study shows the efficacy of EGFR targeting with PIC constructs and suggests approaches to improve PIC designs and targeting strategies for in vivo photoimmunotherapy. The approach offers the possibility of dual effects via antibody-mediated cytostasis and photoimmunotherapy-based cytotoxicity.161Choi, Y.; McCarthy, J. R.; Weissleder, R.; Tung, C. H. Conjugation of a Photosensitizer to an Oligoarginine-Based Cell-Penetrating Peptide Increases the Efficacy of Photodynamic Therapy. ChemMedChem 2006, 1, 458– 463, DOI: 10.1002/cmdc.200500036[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xjslehuro%253D&md5=d2715b0409f9c17718ab31a0bd6b44f6Conjugation of a photosensitizer to an oligoarginine-based cell-penetrating peptide increases the efficacy of photodynamic therapyChoi, Yongdoo; McCarthy, Jason R.; Weissleder, Ralph; Tung, Ching-HsuanChemMedChem (2006), 1 (4), 458-463CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)To improve the efficiency of intracellular delivery of photosensitizers and the efficacy of photodynamic therapy, a membrane-penetrating arginine oligopeptide (R7) was conjugated to 5-[4-carboxyphenyl]-10,15,20-triphenyl-2,3-dihydroxychlorin (TPC). The resulting conjugate (R7-TPC) enhanced intracellular TPC uptake, which increased proportionally with the incubation time of the conjugate. The water soly. of the highly hydrophobic TPC photosensitizer was also improved after conjugation. Increased phototoxicity of R7-TPC was obsd. after an incubation time of only 30 min. Tumor cells mainly underwent apoptosis at lower concns. of the photosensitizer-polyarginine conjugate, whereas necrotic cell damage became prevalent at higher concns.162Minchinton, A. I.; Tannock, I. F. Drug Penetration in Solid Tumours. Nat. Rev. Cancer 2006, 6, 583– 592, DOI: 10.1038/nrc1893[Crossref], [PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XntFGlu7w%253D&md5=89afe4c91bdf6080f16dc13e4dd1e140Drug penetration in solid tumoursMinchinton, Andrew I.; Tannock, Ian F.Nature Reviews Cancer (2006), 6 (8), 583-592CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. To be most effective anticancer drugs must penetrate tissue efficiently, reaching all the cancer cells that comprise the target population in a concn. sufficient to exert a therapeutic effect. Most research into the resistance of cancers to chemotherapy has concd. on mol. mechanisms of resistance, whereas the role of limited drug distribution within tumors has been neglected. We summarize the evidence that indicates that the distribution of many anticancer drugs in tumor tissue is incomplete, and we suggest strategies that might be used either to improve drug penetration through tumor tissue or to select compds. based on their abilities to penetrate tissue, thereby increasing the therapeutic index.163Greish, K. Enhanced Permeability and Retention (Epr) Effect for Anticancer Nanomedicine Drug Targeting. Methods Mol. Biol. 2010, 624, 25– 37, DOI: 10.1007/978-1-60761-609-2_3[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvVymu78%253D&md5=22dd10c42cbd982a7c2fba9ef399ce53Enhanced permeability and retention (EPR) effect for anticancer nanomedicine drug targetingGreish, KhaledMethods in Molecular Biology (Totowa, NJ, United States) (2010), 624 (Cancer Nanotechnology), 25-37CODEN: MMBIED; ISSN:1064-3745. (Humana Press Inc.)A review. Effective cancer therapy remains one of the most challenging tasks to the scientific community, with little advancement on overall cancer survival landscape during the last two decades. A major limitation inherent to most conventional anticancer chemotherapeutic agents is their lack of tumor selectivity. One way to achieve selective drug targeting to solid tumors is to exploit abnormalities of tumor vasculature, namely hypervascularization, aberrant vascular architecture, extensive prodn. of vascular permeability factors stimulating extravasation within tumor tissues, and lack of lymphatic drainage. Due to their large size, nano-sized macromol. anticancer drugs administered i.v. escape renal clearance. Being unable to penetrate through tight endothelial junctions of normal blood vessels, their concn. builds up in the plasma rendering them long plasma half-life. More importantly, they can selectively extravasate in tumor tissues due to its abnormal vascular nature. Overtime the tumor concn. will build up reaching several folds higher than that of the plasma due to lack of efficient lymphatic drainage in solid tumor, an ideal application for EPR-based selective anticancer nanotherapy. Indeed, this selective high local concn. of nano-sized anticancer drugs in tumor tissues has proven superior in therapeutic effect with minimal side effects in both preclin. and clin. settings.164McNeil, S. E. Nanotechnology for the Biologist. J. Leukocyte Biol. 2005, 78, 585– 594, DOI: 10.1189/jlb.0205074[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVSksbzI&md5=e80230b6a0859315787c2e43dbd74797Nanotechnology for the biologistMcNeil, Scott E.Journal of Leukocyte Biology (2005), 78 (3), 585-594CODEN: JLBIE7; ISSN:0741-5400. (Federation of American Societies for Experimental Biology)A review. Nanotechnol. refers to research and technol. development at the at., mol., and macromol. scale, leading to the controlled manipulation and study of structures and devices with length scales in the 1-100-nm range. Objects at this scale, such as "nanoparticles," take on novel properties and functions that differ markedly from those seen on the bulk scale. The small size, surface tailorability, improved soly., and multifunctionality of nanoparticles open many new research avenues for biologists. The novel properties of nanomaterials offer the ability to interact with complex biol. functions in new ways, operating at the very scale of biomols. This rapidly growing field allows cross-disciplinary researchers the opportunity to design and develop multifunctional nanoparticles that can target, diagnose, and treat diseases such as cancer. Here, the author presents an overview of nanotechnol. for the biologist and discusses "nanotech" strategies and constructs that have already demonstrated in vitro and in vivo efficacy.165Tanaka, M.; Kataoka, H.; Yano, S.; Ohi, H.; Moriwaki, K.; Akashi, H.; Taguchi, T.; Hayashi, N.; Hamano, S.; Mori, Y.; Kubota, E.; Tanida, S.; Joh, T. Antitumor Effects in Gastrointestinal Stromal Tumors Using Photodynamic Therapy With a Novel Glucose-Conjugated Chlorin. Mol. Cancer Ther. 2014, 13, 767– 775, DOI: 10.1158/1535-7163.MCT-13-0393[Crossref], [PubMed], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXls1Gjtbs%253D&md5=c266bcac5b6a7a49d046554f0bcd8728Antitumor Effects in Gastrointestinal Stromal Tumors Using Photodynamic Therapy with a Novel Glucose-Conjugated ChlorinTanaka, Mamoru; Kataoka, Hiromi; Yano, Shigenobu; Ohi, Hiromi; Moriwaki, Kazuhiro; Akashi, Haruo; Taguchi, Takahiro; Hayashi, Noriyuki; Hamano, Shingo; Mori, Yoshinori; Kubota, Eiji; Tanida, Satoshi; Joh, TakashiMolecular Cancer Therapeutics (2014), 13 (4), 767-775CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Except for surgical resection, no effective treatment strategies have been established. Photodynamic therapy (PDT) consists of i.v. administration of a photosensitizer, activated by a specific wavelength of light, which produces reactive oxygen species that directly kill tumor cells. We analyzed the efficacy of PDT using a newly developed photosensitizer, 5,10,15,20-tetrakis [4-[β-d-glucopyranosylthio-2,3,5,6-tetrafluorophenyl]-2,3,[methano[N-methyl] iminomethano]chlorin (H2TFPC-SGlc), for the GIST treatment. Various photosensitizers were administered in vitro to GIST (GIST-T1) and fibroblast (WI-38) cells, followed by irradn., after which cell death was compared. We addnl. established xenograft mouse models with GIST-T1 tumors and examd. the accumulation and antitumor effects of these photosensitizers in vivo. In vitro, the expression of the glucose transporters GLUT1, GLUT3, and GLUT4, the cellular uptake of H2TFPC-SGlc, and apoptosis mediated by PDT with H2TFPC-SGlc were significantly higher in GIST-T1 than in WI-38 cells. In vivo, H2TFPC-SGlc accumulation was higher in xenograft tumors of GIST-T1 cells than in the adjacent normal tissue, and tumor growth was significantly suppressed following PDT. PDT with novel H2TFPC-SGlc is potentially useful for clin. applications about the treatment of GIST. Mol Cancer Ther; 13(4); 767-75. ©2014 AACR.166Jain, R. K. Delivery of Molecular and Cellular Medicine to Solid Tumors. Adv. Drug Delivery Rev. 2001, 46, 149– 168, DOI: 10.1016/S0169-409X(00)00131-9[Crossref], [PubMed], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXitVOhsLw%253D&md5=e8e5acd4b3f7a7c4fe647179537681efDelivery of molecular and cellular medicine to solid tumorsJain, R. K.Advanced Drug Delivery Reviews (2001), 46 (1-3), 149-168CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science Ireland Ltd.)A review, with 151 refs. To reach cancer cells in a tumor, a blood-borne therapeutic mol. or cell must make its way into the blood vessels of the tumor and across the vessel wall into the interstitium, and finally migrate through the interstitium. Unfortunately, tumors often develop in ways that hinder each of these steps. Our research goals are to analyze each of these steps exptl. and theor., and then integrate the resulting information in a unified theor. framework. This paradigm of anal. and synthesis has allowed us to obtain a better understanding of physiol. barriers in solid tumors, and to develop novel strategies to exploit and/or to overcome these barriers for improved cancer detection and treatment.167Decuzzi, P.; Causa, F.; Ferrari, M.; Netti, P. A. The Effective Dispersion of Nanovectors Within the Tumor Microvasculature. Ann. Biomed. Eng. 2006, 34, 633– 641, DOI: 10.1007/s10439-005-9072-6[Crossref], [PubMed], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD283hsVGitw%253D%253D&md5=7cd4bfb5606b3985890de37ee49613abThe effective dispersion of nanovectors within the tumor microvasculatureDecuzzi P; Causa F; Ferrari M; Netti P AAnnals of biomedical engineering (2006), 34 (4), 633-41 ISSN:0090-6964.The effective longitudinal diffusion of nanovectors along non-permeable and permeable capillaries has been studied considering the contribution of molecular and convective diffusion based on the Taylor's theory of shear dispersion. The problem is of importance in the transport of nanovectors used for the intravascular delivery of drugs and contrast agents. It has been shown that for a given capillary size and hemodynamic conditions a critical radius acr exists for which the effective longitudinal diffusion along the capillary has a minimum: Nanovectors with a < acr diffuse mainly by Brownian diffusion whereas nanovectors with a < acr diffuse mainly by convection and the effective diffusion coefficient grows with a. In permeable conduits, the effective diffusion reduces significantly compared to normal non-leaky vessels and it has been derived that acr grows almost linearly with the hydraulic permeability Lp of blood vessels. It has been shown that the blood conduits with the largest effective longitudinal diffusivity could be preferentially targeted by the circulating vectors. Based on these findings, the following strategies are proposed to increase the number of nanovectors targeting the tumor vessels: (i) The use of nanovectors with a critical radius for normal vessels, (ii) the injecting of bolus of nanovectors with different radii, and (iii) the normalization of the tumor vasculature. Finally, it has been emphasized that the size of the vector should be selected depending on the body district where the tumoral mass is developing and on the type, malignancy, and state of the tumor.168Decuzzi, P.; Lee, S.; Bhushan, B.; Ferrari, M. A Theoretical Model for the Margination of Particles Within Blood Vessels. Ann. Biomed. Eng. 2005, 33, 179– 190, DOI: 10.1007/s10439-005-8976-5[Crossref], [PubMed], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M7jvFentw%253D%253D&md5=e7c7371efa9b47fe5532df67119cb308A theoretical model for the margination of particles within blood vesselsDecuzzi P; Lee S; Bhushan B; Ferrari MAnnals of biomedical engineering (2005), 33 (2), 179-90 ISSN:0090-6964.The margination of a particle circulating in the blood stream has been analyzed. The contribution of buoyancy, hemodynamic forces, van der Waals, electrostatic and steric interactions between the circulating particle and the endothelium lining the vasculature has been considered. For practical applications, the contribution of buoyancy, hemodynamic forces and van der Waals interactions should be only taken into account, whilst the effect of electrostatic and steric repulsion becomes important only at very short distances from the endothelium (1-10 nm). The margination speed and the time for margination t(s) have been estimated as a function of the density of the particle relative to blood delta rho, the Hamaker constant A and radius R of the particle. A critical radius Rc exists for which the margination time t(s) has a maximum, which is influenced by both delta rho and A: the critical radius decreases as the relative density increases and the Hamaker constant decreases. Therefore, particles used for drug delivery should have a radius smaller than the critical value (in the range of 100 nm) to facilitate margination and interaction with the endothelium. While particles used as nanoharvesting agents in proteomics or genomics analysis should have a radius close to the critical value to minimize margination and increase their circulation time.169Brigger, I.; Dubernet, C.; Couvreur, P. Nanoparticles in Cancer Therapy and Diagnosis. Adv. Drug Delivery Rev. 2002, 54, 631– 651, DOI: 10.1016/S0169-409X(02)00044-3[Crossref], [PubMed], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmsVeqtrs%253D&md5=cac7e471c5141dfa0ad4972789b47b91Nanoparticles in cancer therapy and diagnosisBrigger, Irene; Dubernet, Catherine; Couvreur, PatrickAdvanced Drug Delivery Reviews (2002), 54 (5), 631-651CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science B.V.)A review. Numerous investigations have shown that both tissue and cell distribution profiles of anticancer drugs can be controlled by their entrapment in submicronic colloidal systems (nanoparticles). The rationale behind this approach is to increase antitumor efficacy, while reducing systemic side-effects. This review provides an update of tumor targeting with conventional or long-circulating nanoparticles. The in vivo fate of these systems, after intravascular or tumoral administration, is discussed, as well as the mechanism involved in tumor regression. Nanoparticles are also of benefit for the selective delivery of oligonucleotides to tumor cells. Moreover, certain types of nanoparticles showed some interesting capacity to reverse MDR resistance, which is a major problem in chemotherapy. The first expts., aiming to decorate nanoparticles with mol. ligand for 'active' targeting of cancerous cells, are also discussed here. The last part of this review focus on the application of nanoparticles in imaging for cancer diagnosis.170Higgins, L. J.; Pomper, M. G. The Evolution of Imaging in Cancer: Current State and Future Challenges. Semin. Oncol. 2011, 38, 3– 15, DOI: 10.1053/j.seminoncol.2010.11.010[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M3jtVSmtw%253D%253D&md5=0b129635cc60a5d7e6177a76bb8c227aThe evolution of imaging in cancer: current state and future challengesHiggins Luke J; Pomper Martin GSeminars in oncology (2011), 38 (1), 3-15 ISSN:.Molecular imaging allows for the remote, noninvasive sensing and measurement of cellular and molecular processes in living subjects. Drawing upon a variety of modalities, molecular imaging provides a window into the biology of cancer from the subcellular level to the patient undergoing a new, experimental therapy. As signal transduction cascades and protein interaction networks become clarified, an increasing number of relevant targets for cancer therapy--and imaging--become available. Although conventional imaging is already critical to the management of patients with cancer, molecular imaging will provide even more relevant information, such as early detection of changes with therapy, identification of patient-specific cellular and metabolic abnormalities, and the disposition of therapeutic, gene-tagged cells throughout the body--all of which will have a considerable impact on morbidity and mortality. This overview discusses molecular imaging in oncology, providing examples from a variety of modalities, with an emphasis on emerging techniques for translational imaging.171Rudin, M.; Rausch, M.; Stoeckli, M. Molecular Imaging in Drug Discovery and Development: Potential and Limitations of Nonnuclear Methods. Mol. Imaging Biol. 2005, 7, 5– 13, DOI: 10.1007/s11307-004-0954-z[Crossref], [PubMed], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M3mvFKktA%253D%253D&md5=d2ebc16692644729abd97b08db0addb9Molecular imaging in drug discovery and development: potential and limitations of nonnuclear methodsRudin Markus; Rausch Martin; Stoeckli MarkusMolecular imaging and biology (2005), 7 (1), 5-13 ISSN:1536-1632.Noninvasive conventional imaging methods are established technologies in modern drug discovery and development providing valuable morphological, physiological, and metabolic information to characterize disease phenotypes, to evaluate the efficacy of therapy and to identify and develop potential biomarkers for clinical drug evaluation. The development of target-specific or molecular imaging has added a new dimension: molecular events such as the target expression, the drug-target interaction, or the activation of signal transduction pathways can be studied in the intact organism with high spatial and temporal resolution. Molecular imaging is inherently a multimodality approach. In this article, we review the role of molecular imaging for drug discovery and development focusing on nonnuclear imaging methods, i.e., magnetic resonance imaging (MRI) and optical imaging techniques based on fluorescence and bioluminescence readouts. Examples discussed are direct visualization of target expression using target-specific ligands or reporter genes, pathway imaging, and cell-trafficking studies.172Kopelman, R.; Lee Koo, Y. E.; Philbert, M.; Moffat, B. A.; Ramachandra Reddy, G.; McConville, P.; Hall, D. E.; Chenevert, T. L.; Bhojani, M. S.; Buck, S. M.; Rehemtulla, A.; Ross, B. D. Multifunctional Nanoparticle Platforms for in Vivo MRI Enhancement and Photodynamic Therapy of a Rat Brain Cancer. J. Magn. Magn. Mater. 2005, 293, 404– 410, DOI: 10.1016/j.jmmm.2005.02.061[Crossref], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXktVagsLw%253D&md5=52521220b800501f8fa2ebe5dffae254Multifunctional nanoparticle platforms for in vivo MRI enhancement and photodynamic therapy of a rat brain cancerKopelman, Raoul; Koo, Yong-Eun Lee; Philbert, Martin; Moffat, Bradford A.; Ramachandra Reddy, G.; McConville, Patrick; Hall, Daniel E.; Chenevert, Thomas L.; Bhojani, Mahaveer Swaroop; Buck, Sarah M.; Rehemtulla, Alnawaz; Ross, Brian D.Journal of Magnetism and Magnetic Materials (2005), 293 (1), 404-410CODEN: JMMMDC; ISSN:0304-8853. (Elsevier B.V.)A paradigm for brain cancer detection, treatment, and monitoring is established. Multifunctional biomedical nanoparticles (30-60 nm) contg. photosensitizer externally deliver reactive oxygen species (ROS) to cancer cells while simultaneously enhancing magnetic resonance imaging (MRI) contrast providing real-time tumor kill measurement. Plasma residence time control and specific cell targeting are achieved. A 5 min treatment in rats halted and even reversed in vivo tumor growth after 3-4 days post-treatment.173Abouelmagd, S. A.; Hyun, H.; Yeo, Y. Extracellularly Activatable Nanocarriers for Drug Delivery to Tumors. Expert Opin. Drug Delivery 2014, 11, 1601– 1618, DOI: 10.1517/17425247.2014.930434[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1eju7%252FI&md5=ca068dddf7992125d0a18b7e3f1e83baExtracellularly activatable nanocarriers for drug delivery to tumorsAbouelmagd, Sara A.; Hyun, Hyesun; Yeo, YoonExpert Opinion on Drug Delivery (2014), 11 (10), 1601-1618CODEN: EODDAW; ISSN:1742-5247. (Informa Healthcare)Introduction: Nanoparticles (NPs) for drug delivery to tumors need to satisfy two seemingly conflicting requirements: they should maintain phys. and chem. stability during circulation and be able to interact with target cells and release the drug at desired locations with no substantial delay. The unique microenvironment of tumors and externally applied stimuli provide a useful means to maintain a balance between the two requirements. Areas covered: We discuss nanoparticulate drug carriers that maintain stable structures in normal conditions but respond to stimuli for the spatiotemporal control of drug delivery. We first define the desired effects of extracellular activation of NPs and frequently used stimuli and then review the examples of extracellularly activated NPs. Expert opinion: Several challenges remain in developing extracellularly activatable NPs. First, some of the stimuli-responsive NPs undergo incremental changes in response to stimuli, losing circulation stability. Second, the applicability of stimuli in clin. settings is limited due to the occasional occurrence of the activating conditions in normal tissues. Third, the construction of stimuli-responsive NPs involves increasing complexity in NP structure and prodn. methods. Future efforts are needed to identify new targeting conditions and increase the contrast between activated and nonactivated NPs while keeping the prodn. methods simple and scalable.174Misri, R.; Meier, D.; Yung, A. C.; Kozlowski, P.; Häfeli, U. O. Development and Evaluation of a Dual-Modality (MRI/SPECT) Molecular Imaging Bioprobe. Nanomedicine 2012, 8, 1007– 1016, DOI: 10.1016/j.nano.2011.10.013[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVymt7rO&md5=0ecd316cf779de554fa192b15e789b29Development and evaluation of a dual-modality (MRI/SPECT) molecular imaging bioprobeMisri, Ripen; Meier, Dominik; Yung, Andrew C.; Kozlowski, Piotr; Hafeli, Urs O.Nanomedicine (New York, NY, United States) (2012), 8 (6), 1007-1016CODEN: NANOBF; ISSN:1549-9634. (Elsevier)Specific bioprobes for single photon emission computed tomog. (SPECT) and magnetic resonance imaging (MRI) have enormous potential for use in cancer imaging in near-future clin. settings. The authors describe the development of dual modality mol. imaging bioprobes, in the form of magnetic nanoparticles (NPs) conjugated to antibodies, for SPECT and MRI of mesothelin-expressing cancers. The bioprobes were developed by conjugating 111In labeled antimesothelin antibody mAbMB to superparamagnetic iron oxide NPs. Our exptl. findings provide evidence that such bioprobes retain their magnetic properties as well as the ability to specifically localize in mesothelin-expressing tumors. It is anticipated that combining SPECT with MR will help obtain both functional and anatomical imaging information with high signal sensitivity and contrast, thereby providing a powerful diagnostic tool for early diagnosis and treatment planning of mesothelin-expressing cancers. This team of investigators presents a dual-modality functionalized contrast material that enables tumor visualization both via MRI and SPECT. Similar systems are likely to be utilized in future cancer research.175Yim, H.; Seo, S.; Na, K. MRI Contrast Agent-Based Multifunctional Materials: Diagnosis and Therapy. J. Nanomater. 2011, 2011, 1, DOI: 10.1155/2011/747196176Jerjes, W.; Upile, T.; Hamdoon, Z.; Nhembe, F.; Bhandari, R.; Mackay, S.; Shah, P.; Mosse, C. A.; AS Brookes, J.; Morley, S.; Hopper, C. Ultrasound-Guided Photodynamic Therapy for Deep Seated Pathologies: Prospective Study. Lasers Surg. Med. 2009, 41, 612– 621, DOI: 10.1002/lsm.20853[Crossref], [PubMed], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1MnpvVWktQ%253D%253D&md5=db0528cd9bc7747a18f199e2161b6f29Ultrasound-guided photodynamic therapy for deep seated pathologies: prospective studyJerjes Waseem; Upile Tahwinder; Hamdoon Zaid; Nhembe Farai; Bhandari Rishi; Mackay Sorcha; Shah Priya; Mosse Charles Alexander; Brookes Jocelyn A S; Morley Simon; Hopper ColinLasers in surgery and medicine (2009), 41 (9), 612-21 ISSN:.INTRODUCTION: Interstitial photodynamic therapy remains an attractive remedial option in minimally invasive surgery. Our aim in this prospective study was to evaluate the outcome following ultrasound-guided iPDT of deep-seated pathologies. Patients' reports on quality of life with clinical and radiological evaluation were the main end point parameters used to assess the outcome. MATERIALS AND METHODS: Sixty-eight patients were referred to the UCLH Head and Neck Centre for treatment of various deep-seated pathologies involving the head and neck region, upper and lower limbs. All patients underwent interstitial photodynamic therapy under general anaesthesia, using 0.15 mg/kg mTHPC as the photosensitising agent. Following treatment, patients were followed-up for a mean of 7 months. RESULTS: All three patients who presented with visual problems reported improvement after treatment. Also, 14/17 patients reported improvement of breathing. Improvement of swallowing was reported by 25/30 patients; while speaking improvement was evident in 16/22 patients and 33/40 reported reduction in the disfigurement caused by their pathology. All five patients with impeded limb function reported some degree of improvement. Clinical assessment showed that half of the patients had 'good response' to the treatment and a third reported 'moderate response' with two patients being free of disease. Radiological assessment comparing imaging 6-week post-PDT to the baseline showed stable pathology with no change in size in 13 patients, minimal response in 18 patients, moderate response in 23 patients and significant response in 11 patients. CONCLUSION: This study on 68 patients with deep-seated pathologies undergoing interstitial photodynamic therapy provided evidence that PDT can be the fourth modality in the management of tissue disease.177Eljamel, M. S.; Goodman, C.; Moseley, H. ALA and Photofrin Fluorescence-Guided Resection and Repetitive PDT in Glioblastoma Multiforme: A Single Centre Phase III Randomised Controlled Trial. Lasers Med. Sci. 2008, 23, 361– 367, DOI: 10.1007/s10103-007-0494-2[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cnis1Cntg%253D%253D&md5=8d9f26ebe7e1d8d3bc5bc5a68757fa44ALA and Photofrin fluorescence-guided resection and repetitive PDT in glioblastoma multiforme: a single centre Phase III randomised controlled trialEljamel M Sam; Goodman Carol; Moseley HarryLasers in medical science (2008), 23 (4), 361-7 ISSN:0268-8921.Glioblastoma multiforme (GBM) carries dismal prognosis and cannot be eradicated surgically because of its wide brain invasion. The objective of this prospective randomised controlled trial was to evaluate ALA and Photofrin fluorescence-guided resection (FGR) and repetitive photodynamic therapy (PDT) in GBM. We recruited 27 patients; 13 were in the study group and 14 were in the control group. The mean survival of the study group was 52.8 weeks compared to 24.6 weeks in the control group (p<0.01). The study group gained on average 20 points on the Karnofsky performance score (p<0.05). There were no differences in complications or hospital stay between the two groups. The mean time to tumour progression was 8.6 months in the study group compared to 4.8 months in the control group (p<0.05). Therefore, ALA and Photofrin fluorescence-guided resection and repetitive PDT offered a worthwhile survival advantage without added risk to patients with GBM. A multicentre randomized controlled trial is warranted to confirm these results.178Mark, J. R.; Gelpi-Hammerschmidt, F.; Trabulsi, E. J.; Gomella, L. G. Blue Light Cystoscopy for Detection and Treatment of Non-Muscle Invasive Bladder Cancer. Can. J. Urol. 2012, 19, 6227– 6231[PubMed], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38rmtVequg%253D%253D&md5=0e67a37ffbd58c696e45864cfb8a6abeBlue light cystoscopy for detection and treatment of non-muscle invasive bladder cancerMark J Ryan; Gelpi-Hammerschmidt Francisco; Trabulsi Edouard J; Gomella Leonard GThe Canadian journal of urology (2012), 19 (2), 6227-31 ISSN:1195-9479.In patients with non-muscle invasive bladder cancer, fluorescence cystoscopy can improve the detection and ablation of bladder tumors. In this paper we describe the technique and practical aspects of hexaminolevulinate (HAL) fluorescence cystoscopy, also known as "blue light cystoscopy".179Mallidi, S.; Spring, B. Q.; Chang, S.; Vakoc, B.; Hasan, T. Optical Imaging, Photodynamic Therapy and Optically Triggered Combination Treatments. Cancer J. (Philadelphia, PA, U. S.) 2015, 21, 194– 205, DOI: 10.1097/PPO.0000000000000117[Crossref], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpvV2qsLk%253D&md5=ad5c6efd2cb629c90e146acea94c1714Optical Imaging, Photodynamic Therapy and Optically Triggered Combination TreatmentsMallidi, Srivalleesha; Spring, Bryan Q.; Chang, Sung; Vakoc, Benjamin; Hasan, TayyabaCancer Journal (Philadelphia, PA, United States) (2015), 21 (3), 194-205CODEN: CAJOCB; ISSN:1528-9117. (Lippincott Williams & Wilkins)A review. Optical imaging is becoming increasingly promising for real-time image-guided resections, and combined with photodynamic therapy (PDT), a photochem.-based treatment modality, optical approaches can be intrinsically "theranostic.". Challenges in PDT include precise light delivery, dosimetry, and photosensitizer tumor localization to establish tumor selectivity, and like all other modalities, incomplete treatment and subsequent activation of mol. escape pathways are often attributable to tumor heterogeneity. Key advances in mol. imaging, target-activatable photosensitizers, and optically active nanoparticles that provide both cytotoxicity and a drug release mechanism have opened exciting avenues to meet these challenges. The focus of the review is optical imaging in the context of PDT, but the general principles presented are applicable to many of the conventional approaches to cancer management. We highlight the role of optical imaging in providing structural, functional, and mol. information regarding photodynamic mechanisms of action, thereby advancing PDT and PDT-based combination therapies of cancer. These advances represent a PDT renaissance with increasing applications of clin. PDT as a frontline cancer therapy working in concert with fluorescence-guided surgery, chemotherapy, and radiation.180Mallidi, S.; Anbil, S.; Lee, S.; Manstein, D.; Elrington, S.; Kositratna, G.; Schoenfeld, D.; Pogue, B.; Davis, S. J.; Hasan, T. Photosensitizer Fluorescence and Singlet Oxygen Luminescence as Dosimetric Predictors of Topical 5-Aminolevulinic Acid Photodynamic Therapy Nduced Clinical Erythema. J. Biomed. Opt. 2014, 19, 028001, DOI: 10.1117/1.JBO.19.2.028001[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXosVyntrc%253D&md5=ba85d03716a9b1d68d1bfcd644d7e19cPhotosensitizer fluorescence and singlet oxygen luminescence as dosimetric predictors of topical 5-aminolevuliniv acid photodynamic therapy induced clinical erythemaMallidi, Srivalleesha; Anbil, Sriram; Lee, Seonkyung; Manstein, Dieter; Elrington, Stefan; Kositratna, Garuna; Schoenfeld, David; Pogue, Brian; Davis, Steven J.; Hasan, TayyabaJournal of Biomedical Optics (2014), 19 (2), 028001/1-028001/13CODEN: JBOPFO; ISSN:1083-3668. (Society of Photo-Optical Instrumentation Engineers)The need for patient-specific photodynamic therapy (PDT) in dermatol. and oncol. applications has triggered several studies that explore the utility of surrogate parameters as predictive reporters of treatment outcome. Although photosensitizer (PS) fluorescence, a widely used parameter, can be viewed as emission from several fluorescent states of the PS (e.g., minimally aggregated and monomeric), we suggest that singlet oxygen luminescence (SOL) indicates only the active PS component responsible for the PDT. Here, the ability of discrete PS fluorescence-based metrics (abs. and percent PS photobleaching and PS re-accumulation post-PDT) to predict the clin. phototoxic response (erythema) resulting from 5-aminolevulinic acid PDT was compared with discrete SOL (DSOL)-based metrics (DSOL counts pre-PDT and change in DSOL counts pre/post-PDT) in healthy human skin. Receiver operating characteristic curve (ROC) analyses demonstrated that abs. fluorescence photobleaching metric (AFPM) exhibited the highest area under the curve (AUC) of all tested parameters, including DSOL based metrics. The combination of dose-metrics did not yield better AUC than AFPM alone. Although sophisticated real-time SOL measurements may improve the clin. utility of SOL-based dosimetry, discrete PS fluorescence-based metrics are easy to implement, and our results suggest that AFPM may sufficiently predict the PDT outcomes and identify treatment nonresponders with high specificity in clin. contexts.181Zhou, X.; Pogue, B. W.; Chen, B.; Demidenko, E.; Joshi, R.; Hoopes, J.; Hasan, T. Pretreatment Photosensitizer Dosimetry Reduces Variation in Tumor Response. Int. J. Radiat. Oncol., Biol., Phys. 2006, 64, 1211– 1220, DOI: 10.1016/j.ijrobp.2005.11.019[Crossref], [PubMed], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xhslyis7k%253D&md5=eb846ddad5549ae5f31580258c3ef873Pretreatment photosensitizer dosimetry reduces variation in tumor responseZhou, Xiaodong; Pogue, Brian W.; Chen, Bin; Demidenko, Eugene; Joshi, Rohan; Hoopes, Jack; Hasan, TayyabaInternational Journal of Radiation Oncology, Biology, Physics (2006), 64 (4), 1211-1220CODEN: IOBPD3; ISSN:0360-3016. (Elsevier Inc.)Photosensitizer uptake variation in photodynamic therapy (PDT) compensates via control of delivered light dose through photodynamic dose calcn. based on online dosimetry of photosensitizer in tissue before treatment. Photosensitizer verteporfin was quantified via multiple fluorescence microprobe measurements immediately before treatment. To compensate individual PDT treatments, photodynamic doses were calcd. on an individual animal basis, by matching the light delivered to provide an equal photosensitizer dose multiplied by light dose. This was completed for the lower quartile, median, and upper quartile of the photosensitizer distribution. PDT-induced tumor responses were evaluated by the tumor regrowth assay. Verteporfin uptake varied considerably among tumors and within a tumor. The coeff. of variation in the surviving fraction was found significantly decreased in groups compensated to the lower quartile (CL-PDT), the median (CM-PDT), and the upper quartile (CU-PDT) of photosensitizer distribution. The CL-PDT group was significantly less effective compared with NC-PDT (Noncompensated PDT), CM-PDT, and CU-PDT treatments. No significant difference in effectiveness was obsd. between NC-PDT, CM-PDT, and CU-PDT treatment groups. This research suggests that accurate quantification of tissue photosensitizer levels and subsequent adjustment of light dose will allow for reduced subject variation and improved treatment consistency.182Zou, J.; Yin, Z.; Wang, P.; Chen, D.; Shao, J.; Zhang, Q.; Sun, L.; Huang, W.; Dong, X. Photosensitizer Synergistic Effects: D-A-D Structured Organic Molecule With Enhanced Fluorescence and Singlet Oxygen Quantum Yield for Photodynamic Therapy. Chem. Sci. 2018, 9, 2188– 2194, DOI: 10.1039/C7SC04694D[Crossref], [PubMed], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFOitLc%253D&md5=e4dcd13bbd81c17fe3266ffaa1dccd94Photosensitizer synergistic effects: D-A-D structured organic molecule with enhanced fluorescence and singlet oxygen quantum yield for photodynamic therapyZou, Jianhua; Yin, Zhihui; Wang, Peng; Chen, Dapeng; Shao, Jinjun; Zhang, Qi; Sun, Liguo; Huang, Wei; Dong, XiaochenChemical Science (2018), 9 (8), 2188-2194CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The development of photosensitizers with high fluorescence intensity and singlet oxygen (1O2) quantum yields (QYs) is of great importance for cancer diagnosis and photodynamic therapy (PDT). Diketopyrrolopyrrole (DPP) and boron dipyrromethene (BODIPY) are two kinds of building block with great potential for PDT. Herein, a novel donor-acceptor-donor (D-A-D) structured org. photosensitizer DPPBDPI with a benzene ring as a p bridge linking DPP and BODIPY has been designed and synthesized. The results indicate that the combination of DPP with BODIPY can simultaneously increase the fluorescence QY (5.0%) and the 1O2 QY (up to 80%) significantly by the synergistic effect of the two photosensitizers. By nanopptn., DPPBDPI can form uniform nanoparticles (NPs) with a diam. of less than 100 nm. The obtained NPs not only exhibit high photo-toxicity, but also present negligible dark toxicity towards HeLa cells, demonstrating their excellent photodynamic therapeutic efficacy. In vivo fluorescence imaging shows that DPPBDPI NPs can target the tumor site quickly with the enhanced permeability and retention (EPR) effect and can effectively inhibit tumor growth using photodynamic therapy even with low doses (0.5 mg kg-1). The enhanced imaging and photodynamic performance of DPPBDPI suggest that the synergistic effect of DPP and BODIPY provides a novel theranostic platform for cancer diagnosis and photodynamic therapy.183Pereira, N. A. M.; Laranjo, M.; Casalta-Lopes, J.; Serra, A. C.; Piñeiro, M.; Pina, J.; Seixas de Melo, J. S.; Senge, M. O.; Botelho, M. F.; Martelo, L.; Burrows, H. D.; Pinho E Melo, T. M. V. D. Platinum(II) Ring-Fused Chlorins as Near-Infrared Emitting Oxygen Sensors and Photodynamic Agents. ACS Med. Chem. Lett. 2017, 8, 310– 315, DOI: 10.1021/acsmedchemlett.6b00476[ACS Full Text], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjt1Wltr0%253D&md5=77b58a23768f743c859a19a3a3ebec40Platinum(II) Ring-Fused Chlorins as Near-Infrared Emitting Oxygen Sensors and Photodynamic AgentsPereira, Nelson A. M.; Laranjo, Mafalda; Casalta-Lopes, Joao; Serra, Armenio C.; Pineiro, Marta; Pina, Joao; Seixas de Melo, J. Sergio; Senge, Mathias O.; Botelho, M. Filomena; Martelo, Liliana; Burrows, Hugh D.; Pinho e Melo, Teresa M. V. D.ACS Medicinal Chemistry Letters (2017), 8 (3), 310-315CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Novel near-IR luminescent compds. based on platinum(II) 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins are described. These compds. have high photostability and display light emission, in particular simultaneous fluorescence and phosphorescence emission in soln. at room temp., in the biol. relevant 700-850 nm red and near-IR (NIR) spectral region, making them excellent materials for biol. imaging. The simultaneous presence of fluorescence and phosphorescence emission at room temp., with the phosphorescence strongly quenched by oxygen whereas fluorescence remains unaffected, allows these compds. to be used as ratiometric oxygen sensors in chem. and biol. media. Both steady-state (fluorescence vs. phosphorescence intensities) and dynamic (dependence of phosphorescence lifetimes upon oxygen concn.) luminescence approaches can be used. Photocytotoxicity studies against human melanocytic melanoma cells (A375) indicate that these compds. display potential as photosensitizers in photodynamic therapy.184Stefflova, K.; Chen, J.; Zheng, G. Using Molecular Beacons for Cancer Imaging and Treatment. Front. Biosci., Landmark Ed. 2007, 12, 4709– 4721, DOI: 10.2741/2420[Crossref], [PubMed], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXms1KltL4%253D&md5=8c5386aa2557ff3d9173e535b1abda12Using molecular beacons for cancer imaging and treatmentStefflova, Klara; Chen, Juan; Zheng, GangFrontiers in Bioscience (2007), 12 (), 4709-4721CODEN: FRBIF6; ISSN:1093-4715. (Frontiers in Bioscience)A review. Mol. beacons are essentially all probes that illuminate particular cellular target or cells with similar characteristics. In this review we focus on those mol. beacons that use near-IR fluorescence imaging (NIRF-I) to identify the unique cellular and metabolic markers characteristic of cancer. They employ various delivery and activation pathways, selectively or specifically targeting proliferating and immortal cancer cells. These beacons can either be used in an imaging step sep. from therapy or they can intimately connect these two steps into a single process. Matching cancer therapy to NIRF-I is photodynamic therapy (PDT) that uses the light-triggered phototoxic properties of some porphyrin-based dyes. Guided by beacon's restored fluorescence, the PDT laser could be focused on affected sites, killing the cancer cells using the enhanced photoactivity of the same beacon. Or vice versa-the restored fluorescence from the cleaved beacon could be used as an indication of the beacon's own therapeutic success, imaging the post-PDT apoptotic cells.185Pineiro, M.; Pereira, M. M.; Rocha Gonsalves, A. M. D. A.; Arnaut, L. G.; Formosinho, S. J. Singlet Oxygen Quantum Yields From Halogenated Chlorins: Potential New Photodynamic Therapy Agents. J. Photochem. Photobiol., A 2001, 138, 147– 157, DOI: 10.1016/S1010-6030(00)00382-8[Crossref], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhtlCqtLw%253D&md5=8eb00d9fb67c4ee0cc18a3d6064c77acSinglet oxygen quantum yields from halogenated chlorins: potential new photodynamic therapy agentsPineiro, Marta; Pereira, Mariette M.; Gonsalves, A. M. d'A. Rocha; Arnaut, Luis G.; Formosinho, Sebastiao J.Journal of Photochemistry and Photobiology, A: Chemistry (2001), 138 (2), 147-157CODEN: JPPCEJ; ISSN:1010-6030. (Elsevier Science S.A.)Flash photolysis and photoacoustic calorimetry were used to measure the energy-transfer rates and singlet oxygen quantum yields originated by the triplet states of halogenated tetrakisphenylporphyrins and related chlorins in aerated toluene. The chlorins (λmax ≈ 660 nm, ε ≈ 3 × 104 M-1-cm-1) have long-lived triplet states (> 12 μs) in the absence of mol. oxygen, and in its presence the singlet oxygen prodn. quantum yields of the 2-chloro- and 2,6-dichlorophenyl derivs. are 0.89 ± 0.05 and 0.98 ± 0.02, resp. The high absorptivity in the red, the photostability and the efficiency of these chlorins in producing singlet oxygen suggests a ground for the development of better sensitizers for photodynamic therapy.186Serra, A.; Pineiro, M.; Santos, C. I.; Rocha Gonsalves, A. M. D. A.; Abrantes, M.; Laranjo, M.; Botelho, M. F. In Vitro Photodynamic Activity of 5,15-Bis(3-Hydroxyphenyl)Porphyrin and Its Halogenated Derivatives Against Cancer Cells. Photochem. Photobiol. 2010, 86, 206– 212, DOI: 10.1111/j.1751-1097.2009.00622.x[Crossref], [PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlKms7g%253D&md5=d421afa9cc986d2120abc9b6cde75632In vitro photodynamic activity of 5,15-bis(3-hydroxyphenyl)porphyrin and its halogenated derivatives against cancer cellsSerra, Armenio; Pineiro, Marta; Santos, Catarina Isabel; Gonsalves, Antonio Manuel d'A. Rocha; Abrantes, Margarida; Laranjo, Mafalda; Botelho, Maria FilomenaPhotochemistry and Photobiology (2010), 86 (1), 206-212CODEN: PHCBAP; ISSN:0031-8655. (Wiley-Blackwell)5,15-Diarylporphyrins (1-5) with hydroxyl groups and halogens as substituents were prepd. by condensation between unsubstituted dipyrromethane and halogenated m-hydroxybenzaldehydes. Photophys. properties show that the non-halogenated porphyrin 1 has higher fluorescence yield but lower singlet oxygen formation quantum yield than the halogenated derivs. due to the heavy atom effect. The in vitro activity of these derivs. was tested against WiDr colorectal adenocarcinoma and A375 melanoma cancer cells. All porphyrins present a much higher phototoxicity than Photofrin with IC50 values lower than the 50 nM level for WiDr cells and 25 nM level for A375 cancer cells. The most photoactive compd. is the non-halogenated porphyrin 1 which also presents the highest uptake. Halogenated derivs. present much lower uptakes than 1. However, their photoactivity is similar to compd. 1 showing that their intrinsic photoactivity (ISP) is very high. Iodinated compd. 4 presents the highest ISP. The greater ability of these porphyrins to destroy cancer cells could be related to their photophys. and photochem. properties.187Serra, A. C.; Pineiro, M.; Rocha Gonsalves, A. M. d. A.; Abrantes, M.; Laranjo, M.; Santos, A. C.; Botelho, M. F. Halogen Atom Effect on Photophysical and Photodynamic Characteristics of Derivatives of 5,10,15,20-Tetrakis(3-Hydroxyphenyl)Porphyrin. J. Photochem. Photobiol., B 2008, 92, 59– 65, DOI: 10.1016/j.jphotobiol.2008.04.006[Crossref], [PubMed], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosFSktrk%253D&md5=03a8fc2a808fd2fcbdfdbfbfd1074981Halogen atom effect on photophysical and photodynamic characteristics of derivatives of 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrinSerra, A. C.; Pineiro, M.; Rocha Gonsalves, A. M. d'A.; Abrantes, M.; Laranjo, M.; Santos, A. C.; Botelho, M. F.Journal of Photochemistry and Photobiology, B: Biology (2008), 92 (1), 59-65CODEN: JPPBEG; ISSN:1011-1344. (Elsevier B.V.)Brominated and iodinated derivs. of 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin were synthesized directly from the corresponding aldehydes. Photophys. and photochem. properties, singlet oxygen formation quantum yields, photobleaching and log P were measured. Cellular uptake measurements and cytotoxicity assays on WiDr and A375 tumor cell lines were performed. 5,10,15,20-Tetrakis(2-bromo-5-hydroxyphenyl)porphyrin showed the best cytotoxicity with values of IC50 of 113 nM over WiDr cells and 52 nM over A375 cells.188Stefflova, K.; Li, H.; Chen, J.; Zheng, G. Peptide-Based Pharmacomodulation of a Cancer-Targeted Optical Imaging and Photodynamic Therapy Agent. Bioconjugate Chem. 2007, 18, 379– 388, DOI: 10.1021/bc0602578[ACS Full Text], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhs1Sqt78%253D&md5=8bf63060a689033252e06f42e0f8b4d4Peptide-Based Pharmacomodulation of a Cancer-Targeted Optical Imaging and Photodynamic Therapy AgentStefflova, Klara; Li, Hui; Chen, Juan; Zheng, GangBioconjugate Chemistry (2007), 18 (2), 379-388CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)We designed and synthesized a folate receptor-targeted, water-sol., and pharmacomodulated photodynamic therapy (PDT) agent that selectively detects and destroys the targeted cancer cells while sparing normal tissue. This was achieved by minimizing the normal organ uptake (e.g., liver and spleen) and by discriminating between tumors with different levels of folate receptor (FR) expression. This construct (Pyro-peptide-Folate, PPF) is composed of three components: (1) pyropheophorbide a (Pyro) as an imaging and therapeutic agent, (2) peptide sequence as a stable linker and modulator improving the delivery efficiency, and (3) Folate as a homing mol. targeting FR-expressing cancer cells. We obsd. an enhanced accumulation of PPF in KB cancer cells (FR+) compared to HT 1080 cancer cells (FR-), resulting in a more effective post-PDT killing of KB cells over HT 1080 or normal CHO cells. The accumulation of PPF in KB cells can be up to 70% inhibited by an excess of free folic acid. The effect of Folate on preferential accumulation of PPF in KB tumors (KB vs HT 1080 tumors 2.5:1) was also confirmed in vivo. In contrast to that, no significant difference between the KB and HT 1080 tumor was obsd. in case of the untargeted probe (Pyro-peptide, PP), eliminating the potential influence of Pyro's own nonspecific affinity to cancer cells. More importantly, we found that incorporating a short peptide sequence considerably improved the delivery efficiency of the probe-a process we attributed to a possible peptide-based pharmacomodulation-as was demonstrated by a 50-fold redn. in PPF accumulation in liver and spleen when compared to a peptide-lacking probe (Pyro-K-Folate, PKF). This approach could potentially be generalized to improve the delivery efficiency of other targeted mol. imaging and photodynamic therapy agents.189Wilson, B. C.; Van Lier, J. E. Radiolabelled Photosensitizers for Tumour Imaging and Photodynamic Therapy. J. Photochem. Photobiol., B 1989, 3, 459, DOI: 10.1016/1011-1344(89)80052-1[Crossref], [PubMed], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXkvFartLg%253D&md5=b72280d15f3fc1e0322090d2fd0d9365Radiolabelled photosensitizers for tumor imaging and photodynamic therapyWilson, B. C.; Van Lier, J. E.Journal of Photochemistry and Photobiology, B: Biology (1989), 3 (3), 459-63CODEN: JPPBEG; ISSN:1011-1344.A review, with 22 refs., of the use of photosensitizers labeled with 3H, 14C, or short-lived γ- or positron-emitting radionuclides for tumor imaging and noninvasive quantitation of photosensitizers.190Pandey, S. K.; Sajjad, M.; Chen, Y.; Zheng, X.; Yao, R.; Missert, J. R.; Batt, C.; Nabi, H. A.; Oseroff, A. R.; Pandey, R. K. Comparative Positron-Emission Tomography (PET) Imaging and Phototherapeutic Potential of 1 24i- Labeled Methyl- 3-(1’-Iodobenzyloxyethyl) Pyropheophorbide-A vs the Corresponding Glucose and Galactose Conjugates. J. Med. Chem. 2009, 52, 445– 455, DOI: 10.1021/jm8012213[ACS Full Text], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFaisrfO&md5=9e94231ac3c2b0d05a1a032887484f40Comparative Positron-Emission Tomography (PET) Imaging and Phototherapeutic Potential of 124I- Labeled Methyl- 3-(1'-iodobenzyloxyethyl)pyropheophorbide-a vs the Corresponding Glucose and Galactose ConjugatesPandey, Suresh K.; Sajjad, Munawwar; Chen, Yihui; Zheng, Xiang; Yao, Rutao; Missert, Joseph R.; Batt, Carrie; Nabi, Hani A.; Oseroff, Allan R.; Pandey, Ravindra K.Journal of Medicinal Chemistry (2009), 52 (2), 445-455CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In our present study, 3-(1'-m-iodobenzyloxyethyl)pyropheophorbide-a Me ester 1, 3-(1'-m-iodobenzyloxyethyl)-172-{(2-deoxy)glucose}pyropheophorbide-a 2, and 3-(1'-m-iodobenzyloxyethyl)-172-{(1-deoxy)galactose}pyropheophorbide-a 3 were synthesized and converted into the corresponding 124I-labeled analogs by reacting the intermediate trimethyltin analogs with Na124I. Photosensitizers 1-3 were evaluated for the PDT efficacy in C3H mice bearing RIF tumors at variable doses and showed a significant long-term tumor cure. Among the compds. investigated, the non-carbohydrate analog 1 was most effective. These results were in contrast to the in vitro data, where compared to the parent analog the corresponding galactose and glucose derivs. showed enhanced cell kill. Among the corresponding 124I-labeled analogs, excellent tumor images were obtained from compd. 1 in both tumor models (RIF and Colon-26) and the best tumor contrast was obsd. at 72 h after injection. Conjugating a glucose moiety to photosensitizer 1 initially diminished its tumor uptake, whereas with time the corresponding galactose analog showed improved tumor contrast.191Fazaeli, Y.; Jalilian, A. R.; Amini, M. M.; Ardaneh, K.; Rahiminejad, A.; Bolourinovin, F.; Moradkhani, S.; Majdabadi, A. Development of a 68Ga-Fluorinated Porphyrin Complex as a Possible PET Imaging Agent. Nucl. Med. Mol. Imaging 2012, 46, 20– 26, DOI: 10.1007/s13139-011-0109-5[Crossref], [PubMed], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XisFCksbc%253D&md5=3675ff999e45ee7ac1d1ee0eedadadf7Development of a 68Ga-Fluorinated Porphyrin Complex as a Possible PET Imaging AgentFazaeli, Yousef; Jalilian, Amir R.; Amini, Mostafa M.; Ardaneh, Khosro; Rahiminejad, Ali; Bolourinovin, Fatemeh; Moradkhani, Sedigheh; Majdabadi, AbbasNuclear Medicine and Molecular Imaging (2012), 46 (1), 20-26CODEN: NMMIB8; ISSN:1869-3482. (Springer)Aim Due to the interesting pharmacol. properties of porphyrins, the idea of developing a possible tumor imaging agent using PET by incorporating 68Ga into a suitable porphyrin ligand was investigated. Methods 68Ga-labeled 5,10,15,20-tetrakis(pentafluoro-13 phenyl) porphyrin (68Ga-TFPP) was prepd. using freshly eluted [68Ga]GaCl3 obtained from a 68Ge/68Ga generator developed inhouse and 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (H2TFPP) for 60 min at 100°C. Results The complex was prepd. with high radiochem. purity (>99% ITLC, >99% HPLC, specific activity: 13-14 GBq/mmol). Stability of the complex was checked in the final formulation and in human serum for 5 h. The partition coeff. was calcd. for the compd. (log P = 0.62). The biodistribution of the labeled compd. in vital organs of Swiss mice bearing fibrosarcoma tumors was studied using scarification studies and SPECT imaging up to 1 h. The complex was mostly washed out from the circulation through kidneys and liver. The tumor-to-muscle ratio 1 h post injection was 5.13. Conclusion The radiolabeled porphyrin complex demonstrated potential for further imaging studies in other tumor models.192Shi, J.; Liu, T. W. B.; Chen, J.; Green, D.; Jaffray, D.; Wilson, B. C.; Wang, F.; Zheng, G. Transforming a Targeted Porphyrin Theranostic Agent into a PET Imaging Probe for Cancer. Theranostics 2011, 1, 363– 370, DOI: 10.7150/thno/v01p0363[Crossref], [PubMed], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XislaltLY%253D&md5=713db4a73f97eebb1067d39ef50a8494Transforming a targeted porphyrin theranostic agent into a PET imaging probe for cancerShi, Jiyun; Liu, Tracy W. B.; Chen, Juan; Green, David; Jaffray, David; Wilson, Brian C.; Wang, Fan; Zheng, GangTheranostics (2011), 1 (), 363-370CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)Porphyrin based photosensitizers are useful agents for photodynamic therapy (PDT) and fluorescence imaging of cancer. Porphyrins are also excellent metal chelators forming highly stable metallo-complexes making them efficient delivery vehicles for radioisotopes. Here we investigated the possibility of incorporating 64Cu into a porphyrin-peptide-folate (PPF) probe developed previously as folate receptor (FR) targeted fluorescent/PDT agent, and evaluated the potential of turning the resulting 64Cu-PPF into a positron emission tomog. (PET) probe for cancer imaging. Noninvasive PET imaging followed by radioassay evaluated the tumor accumulation, pharmacokinetics and biodistribution of 64Cu-PPF. 64Cu-PPF uptake in FR-pos. tumors was visible on small-animal PET images with high tumor-to-muscle ratio (8.88 ± 3.60) obsd. after 24 h. Competitive blocking studies confirmed the FR-mediated tracer uptake by the tumor. The ease of efficient 64Cu-radiolabeling of PPF while retaining its favorable biodistribution, pharmacokinetics and selective tumor uptake, provides a robust strategy to transform tumor-targeted porphyrin-based photosensitizers into PET imaging probes.193Tamura, K.; Kurihara, H.; Yonemori, K.; Tsuda, H.; Suzuki, J.; Kono, Y.; Honda, N.; Kodaira, M.; Yamamoto, H.; Yunokawa, M.; Shimizu, C.; Hasegawa, K.; Kanayama, Y.; Nozaki, S.; Kinoshita, T.; Wada, Y.; Tazawa, S.; Takahashi, K.; Watanabe, Y.; Fujiwara, Y. 64Cu-DOTA-Trastuzumab PET Imaging in Patients with HER2-Positive Breast Cancer. J. Nucl. Med. 2013, 54, 1869– 1875, DOI: 10.2967/jnumed.112.118612[Crossref], [PubMed], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVClsrzN&md5=a91a6e5dd49d623379d7976e128a70bf64Cu-DOTA-trastuzumab PET imaging in patients with HER2-positive breast cancerTamura, Kenji; Kurihara, Hiroaki; Yonemori, Kan; Tsuda, Hitoshi; Suzuki, Junko; Kono, Yuzuru; Honda, Natsuki; Kodaira, Makoto; Yamamoto, Harukaze; Yunokawa, Mayu; Shimizu, Chikako; Hasegawa, Koki; Kanayama, Yousuke; Nozaki, Satoshi; Kinoshita, Takayuki; Wada, Yasuhiro; Tazawa, Shusaku; Takahashi, Kazuhiro; Watanabe, Yasuyoshi; Fujiwara, YasuhiroJournal of Nuclear Medicine (2013), 54 (11), 1869-1875CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)The purpose of this study was to det. the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)-pos. tumor images of 64Cu-DOTA-trastuzumab in humans. Methods: PET was performed on 6 patients with primary or metastatic HER2-pos. breast cancer at 1, 24, and 48 h after injection of approx. 130 MBq of the probe 64Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of 64Cu-DOTA-trastuzumab and during the 1-wk follow-up period. Results: According to our results, the best timing for the assessment of 64Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during 64Cu-DOTA-trastuzumab PET was equiv. to that during conventional 18F-FDG PET. The radioactivity in the blood was high, but uptake of 64Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, 64Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood-brain barrier disruptions. In 3 patients, 64Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. Conclusion: The findings of this study indicated that 64Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-pos. lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacol. safety results were acceptable at the dose required for adequate PET imaging.194Aguilar-Ortíz, E.; Jalilian, A. R.; Ávila-Rodríguez, M. A. Porphyrins as Ligands for 64Copper: Background and Trends. MedChemComm 2018, 9, 1577– 1588, DOI: 10.1039/C8MD00263K[Crossref], [PubMed], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFeqt7rE&md5=b85d1917c4841a0ed67197c7c64e99ccPorphyrins as ligands for 64copper: background and trendsAguilar-Ortiz, Edgar; Jalilian, Amir R.; Avila-Rodriguez, Miguel A.MedChemComm (2018), 9 (10), 1577-1588CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Porphyrins and 64Cu have emerged as a novel synergic option for applications in PET mol. imaging. Both the characteristics and photophys. properties of macrocyclic porphyrins and the relatively long half-life of the copper isotope, in addn. to the increased tumor-specific uptake of porphyrins compared to normal cells, make this complex an attractive option not only for diagnosis but also for therapeutic applications. Herein, we present an overview of the latest results on the development of PET agents based on porphyrins and 64Cu, including methods used to improve the selectivity of these macrocycles when conjugated with biol. units such as monoclonal antibodies, peptides or proteins.195Moran, M.; MacDonald, T.; Liu, T.; Forbes, J.; Zhen, G.; Valliant, J. Copper-64-Labeled Porphysomes for PET Imaging. J. Nucl. Med. 2014, 55, 1016196Rousseau, J.; Ali, H.; Lamoureux, G.; Lebel, E.; Van Lier, J. E. Synthesis, Tissue Distribution and Tumor Uptake of 99mTc- and 67Ga- Tetrasulfophthalocyanine. Int. J. Appl. Radiat. Isot. 1985, 36, 709– 716, DOI: 10.1016/0020-708X(85)90041-9[Crossref], [PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXlslClurY%253D&md5=0ba8ebfeec5dd08a43c15449df9af940Synthesis, tissue distribution and tumor uptake of technetium-99m and gallium-67 tetrasulfophthalocyanineRousseau, Jacques; Ali, Hasrat; Lamoureux, Guy; Lebel, Etienne; Van Lier, Johan E.International Journal of Applied Radiation and Isotopes (1985), 36 (9), 709-16CODEN: IJARAY; ISSN:0020-708X.Complexes of tetrasulfophthalocyanine with 99mTc(I), 69Ga, and 67Ga (II) were prepd. by the condensation of sulfophthalic acid with the appropriate metal species. The Ga-complex was also obtained by exchange of the central H atoms of the empty tetrasulfophthalocyanine. The labeled complexes were purified by TLC and characterized by their chromatog. properties. In rabbits and tumor-bearing rats, most of the radioactivity accumulated in the kidneys, liver, ovaries, adrenals, and spleen. Comparison of these distribution patterns with those of 99mTcO4- and 67Ga citrate confirmed the in vivo stability of the labeled complexes. The 67Ga complex reached better tumor-to-blood and tumor-to-muscle ratios than 67Ga citrate.197Li, Z.; Lin, T. P.; Liu, S.; Huang, C. W.; Hudnall, T. W.; Gabbaï, F. P.; Conti, P. S. Rapid Aqueous [18F]-Labeling of a BODIPY Dye for Positron Emission Tomography/Fluorescence Dual Modality Imaging. Chem. Commun. 2011, 47, 9324– 9326, DOI: 10.1039/c1cc13089g[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpvFyksbs%253D&md5=b617f7ac098d9f10c57a46ca434cb277Rapid aqueous [18F]-labeling of a bodipy dye for positron emission tomography/fluorescence dual modality imagingLi, Zibo; Lin, Tzu-Pin; Liu, Shuanglong; Huang, Chiun-Wei; Hudnall, Todd W.; Gabbai, Francois P.; Conti, Peter S.Chemical Communications (Cambridge, United Kingdom) (2011), 47 (33), 9324-9326CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)We report the rapid nucleophilic [18F]-radiolabeling of a bodipy dye in aq. solns. This radiolabeled dye, whose biodistribution and clearance has been studied in mice, is stable in vivo and can be used as a positron emission tomog./fluorescence dual modality imaging agent.198Pandey, R. K.; Goswami, L. N.; Chen, Y.; Gryshuk, A.; Missert, J. R.; Oseroff, A.; Dougherty, T. J. Nature: A Rich Source for Developing Multifunctional Agents. Tumor-Imaging and Photodynamic Therapy. Lasers Surg. Med. 2006, 38, 445– 467, DOI: 10.1002/lsm.20352[Crossref], [PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28zosFCnuw%253D%253D&md5=4d6da90479d36b451478771987e0ab09Nature: a rich source for developing multifunctional agents. Tumor-imaging and photodynamic therapyPandey Ravindra K; Goswami Lalit N; Chen Yihui; Gryshuk Amy; Missert Joseph R; Oseroff Allan; Dougherty Thomas JLasers in surgery and medicine (2006), 38 (5), 445-67 ISSN:0196-8092.The purpose of this review is to call attention in the use of chlorophyll-a and bacteriochlorophyll-a to develop more than 600 photosensitizers (lambda (max) 660 nm-800 nm) during the last 15 years (1990-2005) at the Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo. This article mainly includes the chemistry, preclinical results, and brief clinical data of some of the most effective photosensitizers. The utility of the tumor-avid photosensitizers in developing multimodality agents (imaging and therapy) is also presented.199Pandey, S. K.; Gryshuk, A. L.; Sajjad, M.; Zheng, X.; Chen, Y.; Abouzeid, M. M.; Morgan, J.; Charamisinau, I.; Nabi, H. A.; Oseroff, A.; Pandey, R. K. Multimodality Agents for Tumor Imaging (Pet, Fluorescence) and Photodynamic Therapy. A Possible “See and Treat” Approach. J. Med. Chem. 2005, 48, 6286– 6295, DOI: 10.1021/jm050427m[ACS Full Text], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXpslWrsb0%253D&md5=65ad82b5d6a51f28ac4d0bf998f90e2eMultimodality Agents for Tumor Imaging (PET, Fluorescence) and Photodynamic Therapy. A Possible "See and Treat" ApproachPandey, Suresh K.; Gryshuk, Amy L.; Sajjad, Munawwar; Zheng, Xiang; Chen, Yihui; Abouzeid, Mohei M.; Morgan, Janet; Charamisinau, Ivan; Nabi, Hani A.; Oseroff, Allan; Pandey, Ravindra K.Journal of Medicinal Chemistry (2005), 48 (20), 6286-6295CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Me 3-(1'-m-iodobenzyloxyethyl)-3-devinylpyropheophorbide-a (2), obtained in a sequence of reactions from pyropheophorbide-a (a chlorophyll-a deriv.), was found to be a promising imaging agent and a photosensitizer for photodynamic therapy (PDT). The electrophillic arom. iodination of the corresponding trimethylstannyl intermediate with Na124I in the presence of an Iodogen bead afforded 124I-labeled photosensitizer 4 with >95% radioactive specificity. In addn. to drug-uptake, the light fluence and fluence rate that were used for the light treatment had a significant impact in long-term tumor cure. The iodo photosensitizer 2 (nonlabeled analog of 4) produced 100% tumor cure (5/5 mice were tumor free on day 60) at a dose of 1.5 μmol/kg and a light dose of 128 J/cm2, 14 mW/cm2 for 2.5 h (λmax 665 nm) at 24 h postinjection. The photosensitizer also showed promising tumor fluorescence and PET imaging ability. Our present work demonstrates the utility of the first 124I-labeled photosensitizer as a "multimodality agent", which could further be improved by using more tumor-avid and/or target-specific photosensitizers.200Edrei, R.; Gottfried, V.; van Lier, J. E.; Kimel, S. Sulfonated Phthalocyanines: Photophysical Properties, in Vitro Cell Uptake and Structure-Activity Relationships. J. Porphyrins Phthalocyanines 1998, 2, 191– 199, DOI: 10.1002/(SICI)1099-1409(199805/06)2:3<191::AID-JPP65>3.3.CO;2-W[Crossref], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXlsFOnsbw%253D&md5=415dfb6b9a0e96142f8df650beb9b79cSulfonated phthalocyanines: photophysical properties, in vitro cell uptake and structure-active relationshipsEdrei, R.; Gottfried, V.; Van Lier, J. E.; Kimel, S.Journal of Porphyrins and Phthalocyanines (1998), 2 (3), 191-199CODEN: JPPHFZ; ISSN:1088-4246. (John Wiley & Sons Ltd.)Aluminum phthalocyanines sulfonated to a different degree (AlPcSn) and consisting of various isomeric species were studied by spectroscopic techniques to det. their tendencies to form dimers and aggregates. These characteristics were compared with the cell-penetrating properties of the species, using the Ehrlich ascites mouse tumor cell line, to arrive at structure-activity relationships. AlPcSn prepns. consisting of the least no. of isomeric species exhibited the highest tendency to form dimers and aggregates, whereas the more complex prepns., consisting of many isomeric products, showed more consistent monomeric features in aq. environments. Uptake in cells was shown to correlate well with the overall hydrophobicity of the prepn. and inversely with its degree of aggregation in the extracellular environment. Among the purified, single isomeric AlPcSn the amphiphilic disulfonated AlPcS2a, enriched in positional isomers featuring sulfonate groups on adjacent phthalic subunits, showed the best membrane-penetrating properties. Even higher cell uptake was obsd. for the AlPcS2mix reflecting a combination of optimal lipophilicity and a low degree of aggregation. Similarly, in the case of AlPcS4, the pure isomeric compd. showed less cell uptake than the mixed isomeric prepn. of similar hydrophobicity, reflecting the higher degree of aggregation invoked by its sym. structure. Our data indicate that mixed sulfonated phthalocyanine prepns. may exert higher photodynamic efficacy in biol. applications as compared to the pure isomeric constituents.201Chan, W. M.; Lim, T. H.; Pece, A.; Silva, R.; Yoshimura, N. Verteporfin PDT for Non-Standard Indications-A Review of Current Literature. Graefe's Arch. Clin. Exp. Ophthalmol. 2010, 248, 613– 626, DOI: 10.1007/s00417-010-1307-z[Crossref], [PubMed], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjvFSnuro%253D&md5=1c222766382e77ff435921f559831d58Verteporfin PDT for non-standard indications-a review of current literatureChan, Wai Man; Lim, Tock-Han; Pece, Alfredo; Silva, Rufino; Yoshimura, NagahisaGraefe's Archive for Clinical and Experimental Ophthalmology (2010), 248 (5), 613-626CODEN: GACODL; ISSN:0721-832X. (Springer)A review. Background: Verteporfin photodynamic therapy (PDT) is approved for the treatment of predominantly classic subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD), as well as for subfoveal CNV due to pathol. myopia and ocular histoplasmosis syndrome. Verteporfin PDT addresses the underlying pathol. of ocular vascular disorders through its angio-occlusive mechanism of action, which reduces both visual acuity loss and the underlying leakage assocd. with lesions. Verteporfin PDT has also been assocd. with encouraging treatment outcomes in case studies involving patients with choroidal vascular disorders such as polypoidal choroidal vasculopathy, central serous chorioretinopathy, choroidal haemangioma, angioid streaks, and inflammatory CNV, i.e. conditions currently considered as non-std. indications of verteporfin PDT. In many studies, outcomes were better than expected based on the natural courses of each of these conditions. Although the anti-vascular endothelial growth factor (VEGF) therapies, ranibizumab and pegaptanib, have been approved for CNV due to AMD, their role in these other choroidal vascular disorders remains to be established. We summarize current literature that has documented the use of verteporfin PDT in these conditions. Conclusions: The complex pathogenesis of CNV provides a rationale for investigating combination approaches comprising verteporfin PDT and anti-VEGF therapies. Randomized controlled studies are warranted to confirm the preliminary results of verteporfin PDT as a monotherapy or in combination with anti-VEGF therapies in the treatment of a variety of choroidal vascular conditions.202Skupin-Mrugalska, P.; Piskorz, J.; Goslinski, T.; Mielcarek, J.; Konopka, K.; Düzgüneş, N. Current Status of Liposomal Porphyrinoid Photosensitizers. Drug Discovery Today 2013, 18, 776– 784, DOI: 10.1016/j.drudis.2013.04.003[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntV2gsr0%253D&md5=81bccd78bf2fe2cd0a959bd1606d9ca7Current status of liposomal porphyrinoid photosensitizersSkupin-Mrugalska, Paulina; Piskorz, Jaroslaw; Goslinski, Tomasz; Mielcarek, Jadwiga; Konopka, Krystyna; Duzgunes, NejatDrug Discovery Today (2013), 18 (15-16), 776-784CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. The complete eradication of various targets, such as infectious agents or cancer cells, while leaving healthy host cells untouched, is still a great challenge faced in the field of medicine. Photodynamic therapy (PDT) seems to be a promising approach for anticancer treatment, as well as to combat various dermatol. and ophthalmic diseases and microbial infections. The application of liposomes as delivery systems for porphyrinoids has helped overcome many drawbacks of conventional photosensitizers and facilitated the development of novel effective photosensitizers that can be encapsulated in liposomes. The development, preclin. studies and future directions for liposomal delivery of conventional and novel photosensitizers are reviewed.203Yuzhakova, D. V.; Lermontova, S. A.; Grigoryev, I. S.; Muravieva, M. S.; Gavrina, A. I.; Shirmanova, M. V.; Balalaeva, I. V.; Klapshina, L. G.; Zagaynova, E. V. In Vivo Multimodal Tumor Imaging and Photodynamic Therapy With Novel Theranostic Agents Based on the Porphyrazine Framework-Chelated Gadolinium (III) Cation. Biochim. Biophys. Acta, Gen. Subj. 2017, 1861, 3120– 3130, DOI: 10.1016/j.bbagen.2017.09.004[Crossref], [PubMed], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFOrt73I&md5=663fa67992c309e968412b630507401eIn vivo multimodal tumor imaging and photodynamic therapy with novel theranostic agents based on the porphyrazine framework-chelated gadolinium (III) cationYuzhakova, Diana V.; Lermontova, Svetlana A.; Grigoryev, Ilya S.; Muravieva, Maria S.; Gavrina, Alena I.; Shirmanova, Marina V.; Balalaeva, Irina V.; Klapshina, Larisa G.; Zagaynova, Elena V.Biochimica et Biophysica Acta, General Subjects (2017), 1861 (12), 3120-3130CODEN: BBGSB3; ISSN:0304-4165. (Elsevier B.V.)A promising strategy for cancer diagnosis and therapy is the development of an agent for multimodal imaging and treatment. In the present paper we report on two novel multifunctional agents prepd. on the porphyrazine pigment platform using a gadolinium (III) cation chelated by red-fluorescent tetrapyrrole macrocycles (GdPz1 and GdPz2). Spectral and magnetic properties of the compds. were analyzed. Monitoring of GdPz1 and GdPz2 accumulation in the murine colon carcinoma CT26 was performed in vivo using fluorescence imaging and MRI. The photobleaching of GdPz1 or GdPz2 and tumor growth rate after photodynamic therapy (PDT) were assessed. GdPz1 and GdPz2 demonstrated the selective accumulation in tumor that was indicated by higher fluorescence intensity in the tumor area in comparison with the normal tissues. The results of MRI in vivo showed that GdPz1 or GdPz2 provided significant contrast enhancement of the tumor in T1 MR images. PDT with GdPz2 resulted in ∼ 20% decrease in fluorescence intensity of the compd. and the inhibition of tumor growth. We assessed the efficiency of two innovative Gd(III) cation-porphyrazine chelates as bimodal MR and fluorescent probes and photosensitizers for PDT and showed their potentials for tumor diagnostics and treatment. Water-sol. structures simple in prepn. and administration into the body represent special interest for theranostics of tumors. Novel porphyrazine macrocycles chelating a central gadolinium cation demonstrated a good prospect as effective multimodal agents, representing a new approach to MRI and fluorescence imaging guided PDT.204Lim, E. K.; Kim, T.; Paik, S.; Haam, S.; Huh, Y. M.; Lee, K. Nanomaterials for Theranostics: Recent Advances and Future Challenges. Chem. 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Rev. 2010, 110, 3146– 3195, DOI: 10.1021/cr9003538[ACS Full Text], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjtFOqsr4%253D&md5=ae6a5921dd5db0eaae335ac40a12141aMultimodality Imaging Probes: Design and ChallengesLouie, AngeliqueChemical Reviews (Washington, DC, United States) (2010), 110 (5), 3146-3195CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review.206Edwards, W. B.; Xu, B.; Akers, W.; Cheney, P. P.; Liang, K.; Rogers, B. E.; Anderson, C. J.; Achilefu, S. Agonist - Antagonist Dilemma in Molecular Imaging: Evaluation of a Monomolecular Multimodal Imaging Agent for the Somatostatin Receptor. Bioconjugate Chem. 2008, 19, 192– 200, DOI: 10.1021/bc700291m[ACS Full Text], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlejsbnN&md5=e8df35629b7e2d69c8d1a896b0122557Agonist-Antagonist Dilemma in Molecular Imaging: Evaluation of a Monomolecular Multimodal Imaging Agent for the Somatostatin ReceptorEdwards, W. Barry; Xu, Baogang; Akers, Walter; Cheney, Philip P.; Liang, Kexian; Rogers, Buck E.; Anderson, Carolyn J.; Achilefu, SamuelBioconjugate Chemistry (2008), 19 (1), 192-200CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)The combination of different imaging modalities, each providing information according to its strengths, can be a powerful method for diagnosing diseases. We have synthesized a monomol. multimodal imaging agent (MOMIA), LS172, contg. a subtype-2 somatostatin receptor (SSTr2)-avid peptide (Y3-octreotate or Y3-TATE), a radiometal chelating group (DOTA) and a near-IR (NIR) fluorescent dye (cypate). In addn. to optical methods, radiolabeling LS172 with 64Cu and 177Lu provides a strategy for in vitro evaluation or in vivo multimodal imaging by positron emission tomog. (PET) and single photon emission computed tomog. (SPECT), resp. Detn. of the binding affinity of LS172, natCu- and natLu-LS172 in SSTr2-transfected A427 cells (A427-7) showed that they all displayed high binding affinity toward SSTr2 with Ki values of 0.234 nM, 11.5 nM, and 2.15 nM resp. In contrast to cypate-labeled Y3-TATE (cytate), fluorescence microscopy showed that LS172 and natCu-LS172 accumulate modestly in A427-7 cells by SSTr2-mediated endocytosis, in spite of their relatively high binding affinity. In vivo, the biodistribution of the SSTr2 receptor specific 64Cu- and 177Lu-LS172 in AR42J tumor-bearing rats exhibited low (≤1% ID/g) accumulation in tumor tissue. Clearance from circulation was predominantly hepatobiliary (>90% ID/liver). Both optical and radionuclear biodistribution studies showed a similar in vivo distribution profile. Surprisingly, the strong binding of LS172 to SSTr2 did not translate into high SSTr2-mediated endocytosis in cells or uptake in tumor in vivo. Considering that LS172 is a putative antagonist, the poor accumulation of the labeled MOMIAs in SSTr2 pos. tumor tissue supports the paradigm that agonists with their concomitant internalization favors appreciable target tissue accumulation of receptor-specific ligands.207Walia, S.; Acharya, A. Silica Micro/Nanospheres for Theranostics: From Bimodal MRI and Fluorescent Imaging Probes to Cancer Therapy. Beilstein. Beilstein J. Nanotechnol. 2015, 6, 546– 558, DOI: 10.3762/bjnano.6.57[Crossref], [PubMed], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXls1Kks74%253D&md5=5a33b284c15ad7e9430817ca39abf9eeSilica micro/nanospheres for theranostics: from bimodal MRI and fluorescent imaging probes to cancer therapyWalia, Shanka; Acharya, AmitabhaBeilstein Journal of Nanotechnology (2015), 6 (), 546-558CODEN: BJNEAH; ISSN:2190-4286. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)Nano-theranostics offer remarkable potential for future biomedical technol. with simultaneous applications for diagnosis and therapy of disease sites. Through smart and careful chem. modifications of the nanoparticle surface, these can be converted to multifunctional tiny objects which in turn can be used as vehicle for delivering multimodal imaging agents and therapeutic material to specific target sites in vivo. In this sense, bimodal imaging probes that simultaneously enable magnetic resonance imaging and fluorescence imaging have gained tremendous attention because disease sites can be characterized quick and precisely through synergistic multimodal imaging. But such hybrid nanocomposite materials have limitations such as low chem. stability (magnetic component) and harsh cytotoxic effects (fluorescent component) and, hence, require a biocompatible protecting agent. Silica micro/nanospheres have shown promise as protecting agent due to the high stability and low toxicity. This review will cover a full description of MRI-active and fluorescent multifunctional silica micro/nanospheres including the design of the probe, different characterization methods and their application in imaging and treatment in cancer.208Pandey, S. K.; Kaur, J.; Easwaramoorthy, B.; Shah, A.; Coleman, R.; Mukherjee, J. Multimodality Imaging Probe for Positron Emission Tomography and Fluorescence Imaging Studies. Mol. Imaging 2014, 13, 1– 7, DOI: 10.2310/7290.2014.00005[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cjisFamsg%253D%253D&md5=64af2b6bc545e1b689b670f71e5f7affMultimodality imaging probe for positron emission tomography and fluorescence imaging studiesPandey Suresh K; Kaur Jasmeet; Easwaramoorthy Balu; Shah Ankur; Coleman Robert; Mukherjee JogeshwarMolecular imaging (2014), 13 (), 1-7 ISSN:.Our goal is to develop multimodality imaging agents for use in cell tracking studies by positron emission tomography (PET) and optical imaging (OI). For this purpose, bovine serum albumin (BSA) was complexed with biotin (histologic studies), 5(6)-carboxyfluorescein, succinimidyl ester (FAM SE) (OI studies), and diethylenetriamine pentaacetic acid (DTPA) for chelating gallium 68 (PET studies). For synthesis of BSA-biotin-FAM-DTPA, BSA was coupled to (+)-biotin N-hydroxysuccinimide ester (biotin-NHSI). BSA-biotin was treated with DTPA-anhydride and biotin-BSA-DTPA was reacted with FAM. The biotin-BSA-DTPA-FAM was reacted with gallium chloride 3 to 5 mCi eluted from the generator using 0.1 N HCl and was passed through basic resin (AG 11 A8) and 150 μCi (100 μL, pH 7-8) was incubated with 0.1 mg of FAM conjugate (100 μL) at room temperature for 15 minutes to give 68Ga-BSA-biotin-DTPA-FAM. A shaved C57 black mouse was injected with FAM conjugate (50 μL) at one flank and FAM-68Ga (50 μL, 30 μCi) at the other. Immediately after injection, the mouse was placed in a fluorescence imaging system (Kodak In-Vivo F, Bruker Biospin Co., Woodbridge, CT) and imaged (λex: 465 nm, λem: 535 nm, time: 8 seconds, Xenon Light Source, Kodak). The same mouse was then placed under an Inveon microPET scanner (Siemens Medical Solutions, Knoxville, TN) injected (intravenously) with 25 μCi of 18F and after a half-hour (to allow sufficient bone uptake) was imaged for 30 minutes. Molecular weight determined using matrix-associated laser desorption ionization (MALDI) for the BSA sample was 66,485 Da and for biotin-BSA was 67,116 Da, indicating two biotin moieties per BSA molecule; for biotin-BSA-DTPA was 81,584 Da, indicating an average of 30 DTPA moieties per BSA molecule; and for FAM conjugate was 82,383 Da, indicating an average of 1.7 fluorescent moieties per BSA molecule. Fluorescence imaging clearly showed localization of FAM conjugate and FAM-68Ga at respective flanks of the mouse, whereas only a hot spot at the expected flank (FAM-68Ga injection site) was observed in microPET imaging. Our results suggest that BSA-biotin-DTPA-FAM may function as a multiprobe for PET and fluorescence imaging. Experiments are currently in progress to demonstrate cell tracking using both optical and nuclear imaging.209Wolfbeis, O. S. An Overview of Nanoparticles Commonly Used in Fluorescent Bioimaging. Chem. Soc. Rev. 2015, 44, 4743– 4768, DOI: 10.1039/C4CS00392F[Crossref], [PubMed], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVGisrs%253D&md5=c657579740ee90d89e452ef3e6169f78An overview of nanoparticles commonly used in fluorescent bioimagingWolfbeis, Otto S.Chemical Society Reviews (2015), 44 (14), 4743-4768CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)This article gives an overview of the various kinds of nanoparticles (NPs) that are widely used for purposes of fluorescent imaging, mainly of cells and tissues. Following an introduction and a discussion of merits of fluorescent NPs compared to mol. fluorophores, labels and probes, the article assesses the kinds and specific features of nanomaterials often used in bioimaging. These include fluorescently doped silicas and sol-gels, hydrophilic polymers (hydrogels), hydrophobic org. polymers, semiconducting polymer dots, quantum dots, carbon dots, other carbonaceous nanomaterials, upconversion NPs, noble metal NPs (mainly gold and silver), various other nanomaterials, and dendrimers. Another section covers coatings and methods for surface modification of NPs. Specific examples on the use of nanoparticles in (a) plain fluorescence imaging of cells, (b) targeted imaging, (c) imaging of chem. species, and (d) imaging of temp. are given next. A final section covers aspects of multimodal imaging (such as fluorescence/nmr), imaging combined with drug and gene delivery, or imaging combined with therapy or diagnosis. The electronic supplementary information (ESI) gives specific examples for materials and methods used in imaging, sensing, multimodal imaging and theranostics such as imaging combined with drug delivery or photodynamic therapy. The article contains 273 refs. in the main part, and 157 refs. in the ESI.210Thomas, R.; Park, I. K.; Jeong, Y. Y. Magnetic Iron Oxide Nanoparticles for Multimodal Imaging and Therapy of Cancer. Int. J. Mol. Sci. 2013, 14, 15910– 15930, DOI: 10.3390/ijms140815910[Crossref], [PubMed], [CAS], Google Scholar210https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlWqur7P&md5=7bbea4aca21f1056f9fe7dd35a944d87Magnetic iron oxide nanoparticles for multimodal imaging and therapy of cancerThomas, Reju; Park, In-Kyu; Jeong, Yong YeonInternational Journal of Molecular Sciences (2013), 14 (8), 15910-15930, 21 pp.CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. Superparamagnetic iron oxide nanoparticles (SPION) have emerged as an MRI contrast agent for tumor imaging due to their efficacy and safety. Their utility has been proven in clin. applications with a series of marketed SPION-based contrast agents. Extensive research has been performed to study various strategies that could improve SPION by tailoring the surface chem. and by applying addnl. therapeutic functionality. Research into the dual-modal contrast uses of SPION has developed because these applications can save time and effort by reducing the no. of imaging sessions. In addn. to multimodal strategies, efforts have been made to develop multifunctional nanoparticles that carry both diagnostic and therapeutic cargos specifically for cancer. This review provides an overview of recent advances in multimodality imaging agents and focuses on iron oxide based nanoparticles and their theranostic applications for cancer. Furthermore, we discuss the physiochem. properties and compare different synthesis methods of SPION for the development of multimodal contrast agents.211Vanderesse, D. B. Innovations of Photodynamic Therapy for Brain Tumors: Potential of Multifunctional Nanoparticles. J. Carcinog. Mutagen. 2014, 8, 8, DOI: 10.4172/2157-2518.S8-001212Glasgow, M. D. K.; Chougule, M. B. Recent Developments in Active Tumor Targeted Multifunctional Nanoparticles for Combination Chemotherapy in Cancer Treatment and Imaging. J. Biomed. Nanotechnol. 2015, 11, 1859– 1898, DOI: 10.1166/jbn.2015.2145[Crossref], [PubMed], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XlsVeisA%253D%253D&md5=f662c426459c7228c97c2f924f092916Recent developments in active tumor targeted multifunctional nanoparticles for combination chemotherapy in cancer treatment and imagingGlasgow, Micah D. K.; Chougule, Mahavir B.Journal of Biomedical Nanotechnology (2015), 11 (11), 1859-1898CODEN: JBNOAB; ISSN:1550-7033. (American Scientific Publishers)Nanotechnol. and combination therapy are two major fields that show great promise in the treatment of cancer. The delivery of drugs via nanoparticles helps to improve drug's therapeutic effectiveness while reducing adverse side effects assocd. with high dosage by improving their pharmacokinetics. Taking advantage of mol. markers over-expressing on tumor tissues compared to normal cells, an "active" mol. marker targeted approach would be-beneficial for cancer therapy. These actively targeted nanoparticles would increase drug concn. at the tumor site, improving efficacy while further reducing chemo-resistance. The multidisciplinary approach may help to improve the overall efficacy in cancer therapy. This review article summarizes recent developments of targeted multifunctional nanoparticles in the delivery of various drugs for a combinational chemotherapy approach to cancer treatment and imaging.213Nafiujjaman, M.; Revuri, V.; Nurunnabi, M.; Jae Cho, K.; Lee, Y. K. Photosensitizer Conjugated Iron Oxide Nanoparticles for Simultaneous in Vitro Magneto-Fluorescent Imaging Guided Photodynamic Therapy. Chem. Commun. 2015, 51, 5687– 5690, DOI: 10.1039/C4CC10444G[Crossref], [PubMed], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXislKis7w%253D&md5=11eddb290b15e58a58d1674da5065beePhotosensitizer conjugated iron oxide nanoparticles for simultaneous in vitro magneto-fluorescent imaging guided photodynamic therapyNafiujjaman, Md; Revuri, Vishnu; Nurunnabi, Md; Jae Cho, Kwang; Lee, Yong-kyuChemical Communications (Cambridge, United Kingdom) (2015), 51 (26), 5687-5690CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)In this study, photosensitizer conjugated iron oxide nanoparticles were strategically designed and prepd. for simultaneous PDT and dual-mode fluorescence/MR imaging. The MRI contrast agent Fe3O4 was modified by APTES to functionalize the surface and further to link with heparin-pheophorbide-A conjugates.214Wang, D.; Fei, B.; Halig, L. V.; Qin, X.; Hu, Z.; Xu, H.; Wang, Y. A.; Chen, Z.; Kim, S.; Shin, D. M.; Chen, Z. Targeted Iron-Oxide Nanoparticle for Photodynamic Therapy and Imaging of Head and Neck Cancer. ACS Nano 2014, 8, 6620– 6632, DOI: 10.1021/nn501652j[ACS Full Text], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXps1Wjtbk%253D&md5=0aab744b29a213835df939cd81cfd9dcTargeted Iron-Oxide Nanoparticle for Photodynamic Therapy and Imaging of Head and Neck CancerWang, Dongsheng; Fei, Baowei; Halig, Luma V.; Qin, Xulei; Hu, Zhongliang; Xu, Hong; Wang, Yongqiang Andrew; Chen, Zhengjia; Kim, Sungjin; Shin, Dong M.; Chen, ZhuoACS Nano (2014), 8 (7), 6620-6632CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Photodynamic therapy (PDT) is a highly specific anticancer treatment modality for various cancers, particularly for recurrent cancers that no longer respond to conventional anticancer therapies. PDT has been under development for decades, but light-assocd. toxicity limits its clin. applications. To reduce the toxicity of PDT, we recently developed a targeted nanoparticle (NP) platform that combines a second-generation PDT drug, Pc 4, with a cancer targeting ligand, and iron oxide (IO) NPs. Carboxyl functionalized IO NPs were first conjugated with a fibronectin-mimetic peptide (Fmp), which binds integrin β1. Then the PDT drug Pc 4 was successfully encapsulated into the ligand-conjugated IO NPs to generate Fmp-IO-Pc 4. Our study indicated that both nontargeted IO-Pc 4 and targeted Fmp-IO-Pc 4 NPs accumulated in xenograft tumors with higher concns. than nonformulated Pc 4. As expected, both IO-Pc 4 and Fmp-IO-Pc 4 reduced the size of HNSCC xenograft tumors more effectively than free Pc 4. Using a 10-fold lower dose of Pc 4 than that reported in the literature, the targeted Fmp-IO-Pc 4 NPs demonstrated significantly greater inhibition of tumor growth than nontargeted IO-Pc 4 NPs. These results suggest that the delivery of a PDT agent Pc 4 by IO NPs can enhance treatment efficacy and reduce PDT drug dose. The targeted IO-Pc 4 NPs have great potential to serve as both a magnetic resonance imaging (MRI) agent and PDT drug in the clinic.215Luo, J.; Chen, L. F.; Hu, P.; Chen, Z. N. Tetranuclear Gadolinium(III) Porphyrin Complex as a Theranostic Agent for Multimodal Imaging and Photodynamic Therapy. Inorg. Chem. 2014, 53, 4184– 4191, DOI: 10.1021/ic500238s[ACS Full Text], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltlyks7o%253D&md5=02316e87bcf59cae7357222293e43ccfTetranuclear Gadolinium(III) Porphyrin Complex as a Theranostic Agent for Multimodal Imaging and Photodynamic TherapyLuo, Jian; Chen, Li-Feng; Hu, Ping; Chen, Zhong-NingInorganic Chemistry (2014), 53 (8), 4184-4191CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)We describe herein the elaborate design of a Gd(III)-porphyrin complex as a theranostic agent for multimodal imaging and photodynamic therapy. Far-red-emitting (665 nm) and high relaxivity (14.1 mM-1 s-1) with 107% increase upon binding to HSA (human serum albumin) (29.2 mM-1 s-1) together with efficiently generating singlet oxygen upon exposure to far-red light irradn. at 650 ± 20 nm demonstrate that this Gd(III)-porphyrin complex with four Gd(III)-DTTA units bound to tetraphenylporphyrin acts as a potentially theranostic agent with excellent performance for magnetic resonance imaging, optical imaging, and photodynamic therapy.216Spernyak, J. A.; White, W. H.; Ethirajan, M.; Patel, N. J.; Goswami, L.; Chen, Y.; Turowski, S.; Missert, J. R.; Batt, C.; Mazurchuk, R.; Pandey, R. K. Hexylether Derivative of Pyropheophorbide-a (HPPH) on Conjugating with 3 Gadolinium(III) Aminobenzyldiethylenetriaminepentaacetic Acid Shows Potential for In Vivo Tumor Imaging (MR, Fluorescence) and Photodynamic Therapy. Bioconjugate Chem. 2010, 21, 828– 835, DOI: 10.1021/bc9005317[ACS Full Text], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXksF2lsL0%253D&md5=8a8ac3bdad4a8fccb17ee993184d3e2aHexylether Derivative of Pyropheophorbide-a (HPPH) on Conjugating with 3Gadolinium(III) Aminobenzyldiethylenetriaminepentaacetic Acid Shows Potential for in Vivo Tumor Imaging (MR, Fluorescence) and Photodynamic TherapySpernyak, Joseph A.; White, William H., III; Ethirajan, Manivannan; Patel, Nayan J.; Goswami, Lalit; Chen, Yihui; Turowski, Steven; Missert, Joseph R.; Batt, Carrie; Mazurchuk, Richard; Pandey, Ravindra K.Bioconjugate Chemistry (2010), 21 (5), 828-835CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Conjugates of 3-(1'-hexyloxyethyl)-3-devinyl pyropheophorbide-a (HPPH) with multiple Gd(III)aminobenzyl diethylenetriamine pentacetic acid (ADTPA) moieties were evaluated for tumor imaging and photodynamic therapy (PDT). In vivo studies performed in both mice and rat tumor models resulted in a significant MR signal enhancement of tumors relative to surrounding tissues at 24 h postinjection. The water-sol. (pH: 7.4) HPPH-3Gd(III) ADTPA conjugate demonstrated high potential for tumor imaging by MR and fluorescence. This agent also produced long-term tumor cures via PDT. An in vivo biodistribution study with the corresponding 14C-analog also showed significant tumor uptake 24 h postinjection. Toxicol. evaluations of HPHH-3Gd(III)ADTPA administered at and above imaging/therapeutic doses did not show any evidence of organ toxicity. Our present study illustrates a novel approach for the development of water-sol. "multifunctional agents", demonstrating efficacy for tumor imaging (MR and fluorescence) and phototherapy.217An, F. F.; Chan, M.; Kommidi, H.; Ting, R. Dual PET and Near-Infrared Fluorescence Imaging Probes as Tools for Imaging in Oncology. AJR, Am. J. Roentgenol. 2016, 207, 266– 273, DOI: 10.2214/AJR.16.16181[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s%252FjtFGlsw%253D%253D&md5=cb5e99f9ce1603ec22a002715dfb3ca0Dual PET and Near-Infrared Fluorescence Imaging Probes as Tools for Imaging in OncologyAn Fei-Fei; Chan Mark; Kommidi Harikrishna; Ting RichardAJR. American journal of roentgenology (2016), 207 (2), 266-73 ISSN:.OBJECTIVE: The purpose of this article is to summarize advances in PET fluorescence resolution, agent design, and preclinical imaging that make a growing case for clinical PET fluorescence imaging. CONCLUSION: Existing SPECT, PET, fluorescence, and MRI contrast imaging techniques are already deeply integrated into the management of cancer, from initial diagnosis to the observation and management of metastases. Combined positron-emitting fluorescent contrast agents can convey new or substantial benefits that improve on these proven clinical contrast agents.218Seibold, U.; Wängler, B.; Schirrmacher, R.; Wängler, C. Bimodal Imaging Probes for Combined PET and OI: Recent Developments and Future Directions for Hybrid Agent Development. BioMed Res. Int. 2014, 16, 1, DOI: 10.1155/2014/153741219Nguyen, Q. T.; Tsien, R. Y. Fluorescence-Guided Surgery with Live Molecular Navigation-A New Cutting Edge. Nat. Rev. Cancer 2013, 13, 653– 662, DOI: 10.1038/nrc3566[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1emtrnL&md5=3e2d4d555e5d0cce02178d800a8a3e93Fluorescence-guided surgery with live molecular navigation - a new cutting edgeNguyen, Quyen T.; Tsien, Roger Y.Nature Reviews Cancer (2013), 13 (9), 653-662CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. A glowing new era in cancer surgery may be dawning. Using fluorescently labeled markers, surgical mol. navigation means that tumors and nerves can be displayed in real time intra-operatively in contrasting pseudocolors, which allows more complete tumor resection while preserving important structures. These advances can potentially cause a paradigm shift in cancer surgery, improving patient outcome and decreasing overall health-care costs.220Ghosh, S. C.; Azhdarinia, A. Advances in the Development of Multimodal Imaging Agents for Nuclear/Near-Infrared Fluorescence Imaging. Curr. Med. Chem. 2015, 22, 3390– 3404, DOI: 10.2174/0929867322666150904111214[Crossref], [PubMed], [CAS], Google Scholar220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Ont7nN&md5=3db771838cedeb590f57ddfcdd91b4b6Advances in the Development of Multimodal Imaging Agents for Nuclear/Near-infrared Fluorescence ImagingGhosh, S. C.; Azhdarinia, A.Current Medicinal Chemistry (2015), 22 (29), 3390-3404CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)Multimodal imaging agents were first introduced a decade ago and consist of a targeting moiety that is dual-labeled with radioactive and fluorescent contrast. These compds. allow whole-body and intraoperative imaging to be performed through administration of a single agent and provide complementary diagnostic information that can be used to guide tumor resection. Since their initial evaluation, interest in dual-labeled agents has continued to grow and their design has subsequently evolved alongside the development of novel chelating agents, improved fluorophores, and highly selective coupling techniques for bioconjugate formation. In this review, will discuss how changes in the labeling components and schemes for multimodal agent development have impacted imaging performance and will focus on antibody- and peptide-based agents as models for dual labeling. We will also describe the growing role of modular dual labeling strategies as well as direct labeling methods using radiohalogens.221Zeng, C.; Shang, W.; Wang, K.; Chi, C.; Jia, X.; Fang, C.; Yang, D.; Ye, J.; Fang, C.; Tian, J. Intraoperative Identification of Liver Cancer Microfoci Using a Targeted Near-Infrared Fluorescent Probe for Imaging-Guided Surgery. Sci. Rep. 2016, 6, 21959, DOI: 10.1038/srep21959[Crossref], [PubMed], [CAS], Google Scholar221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjsFegur4%253D&md5=aed0aadd9c9234d51578d5e06051aeccIntraoperative Identification of Liver Cancer Microfoci Using a Targeted Near-Infrared Fluorescent Probe for Imaging-Guided SurgeryZeng, Chaoting; Shang, Wenting; Wang, Kun; Chi, Chongwei; Jia, Xiaohua; Fang, Cheng; Yang, Du; Ye, Jinzuo; Fang, Chihua; Tian, JieScientific Reports (2016), 6 (), 21959CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Difficulties in the highly sensitive detection of tumor microfoci represent a crit. obstacle toward improved surgical intervention in liver cancer. Conventional preoperative imaging methods and surgeons' subjective experience are limited by their inability to effectively detect tumor lesions measuring less than 2 mm; however, intraoperative fluorescence mol. imaging may overcome this limitation. Here, we synthesized an arginine-glycine-aspartic acid (RGD)-conjugated mesoporous silica nanoparticle (MSN) highly loaded with indocyanine green (ICG) dye that could accurately delineate liver cancer margins and provide excellent tumor-to-normal tissue contrast intraoperatively. The increased ICG loading capacity and tumor specificity enabled the identification of residual microtumors and satellite lesions measuring less than 1 mm in living mice. Histol. anal. validated the sensitivity and accuracy of this approach. We believe this technique utilizing a new fluorescent nanoprobe with intraoperative optical imaging may offer a more sensitive and accurate method for liver cancer resection guidance, resulting in better surgical outcomes.222Li, X.; Zhang, X.-N.; Li, X.-D.; Chang, J.; Li, X.; Zhang, X.-N.; Li, X.-D.; Chang, J. Multimodality Imaging in Nanomedicine and Nanotheranostics. Cancer Biol. Med. 2016, 13, 339– 348, DOI: 10.20892/j.issn.2095-3941.2016.0055[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvVWhs74%253D&md5=ab9da73bad6529f9178f0b005e756011Multimodality imaging in nanomedicine and nanotheranosticsLi, Xue; Zhang, Xue-Ning; Li, Xiao-Dong; Chang, JinCancer Biology & Medicine (2016), 13 (3Spec.Iss.), 339-348CODEN: CBMADQ ISSN:. (Tianjin Medical University Cancer Institute and Hospital)Accurate diagnosis of tumors needs much detailed information. However, available single imaging modality cannot provide complete or comprehensive data. Nanomedicine is the application of nanotechnol. to medicine, and multimodality imaging based on nanoparticles has been receiving extensive attention. This new hybrid imaging technol. could provide complementary information from different imaging modalities using only a single injection of contrast agent. In this review, we introduce recent developments in multifunctional nanoparticles and their biomedical applications to multimodal imaging and theragnosis as nanomedicine. Most of the reviewed studies are based on the intrinsic properties of nanoparticles and their application in clin. imaging technol. The imaging techniques include positron emission tomog., single-photon emission computed tomog., computerized tomog., magnetic resonance imaging, optical imaging, and ultrasound imaging.223Durnev, A. D. Toxicology of Nanoparticles. Bull. Bull. Exp. Biol. Med. 2008, 145, 72– 74, DOI: 10.1007/s10517-008-0005-x[Crossref], [PubMed], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cjlvVyltQ%253D%253D&md5=9c2575bd11ba75ab9dcc34002068e548Toxicology of nanoparticlesDurnev A DBulletin of experimental biology and medicine (2008), 145 (1), 72-4 ISSN:0007-4888.The paper considers the basic directions in fundamental and applied studies of the toxic effects of nanoparticles. Of particular importance is the study aimed at evaluation of the dependence of these effects on the shape, size, initial material, surface area, electric charge, and other physicochemical structural peculiarities, as well as on the dosage, mode of application, concentration in the target organ, and duration of action. The differences are stressed in the realization of general toxicity and genotoxicity of nanoparticles and chemical agents. The importance of the development of new methods of preclinical assessment of the safety of therapeutic nanoderivatives is emphasized.224Liu, Z.; Kiessling, F.; Gätjens, J. Advanced Nanomaterials in Multimodal Imaging: Design, Functionalization, and Biomedical Applications. J. Nanomater. 2010, 2010, 1, DOI: 10.1155/2010/894303225Head, H. W.; Dodd, G. D.; Bao, A.; Soundararajan, A.; Garcia-Rojas, X.; Prihoda, T. J.; McManus, L. M.; Goins, B. A.; Santoyo, C. A.; Phillips, W. T. Combination Radiofrequency Ablation and Intravenous Radiolabeled Liposomal Doxorubicin: Imaging and Quantification of Increased Drug Delivery to Tumors. Radiology 2010, 255, 405– 414, DOI: 10.1148/radiol.10090714[Crossref], [PubMed], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c3otlamtQ%253D%253D&md5=347ca11fd7fdf42aa8e5d1a19eaa3b2eCombination radiofrequency ablation and intravenous radiolabeled liposomal Doxorubicin: imaging and quantification of increased drug delivery to tumorsHead Hayden W; Dodd Gerald D 3rd; Bao Ande; Soundararajan Anuradha; Garcia-Rojas Xavier; Prihoda Thomas J; McManus Linda M; Goins Beth A; Santoyo Cristina A; Phillips William TRadiology (2010), 255 (2), 405-14 ISSN:.PURPOSE: To identify, with noninvasive imaging, the zone of radiopharmaceutical uptake after combination therapy with radiofrequency (RF) ablation and intravenous administration of technetium 99m ((99m)Tc) liposomal doxorubicin in a small-animal tumor model, and to quantify and correlate the uptake by using imaging and tissue counting of intratumoral doxorubicin accumulation. MATERIALS AND METHODS: This study was approved by the animal care committee. Two phases of animal experiments were performed. In the first experiment, a single human head-and-neck squamous cell carcinoma tumor was grown in each of 10 male nude rats. Seven of these animals were treated with intravenous (99m)Tc-liposomal doxorubicin followed by RF tumor ablation at a mean temperature of 70 degrees C + or - 2 for 5 minutes, and three were treated with intravenous (99m)Tc-liposomal doxorubicin only. Combination single photon emission computed tomography-computed tomography (SPECT/CT) was performed at 15 minutes, 4 hours, and 20 hours after therapy. In the second experiment, two tumors each were grown in 11 rats, but only one of the tumors was ablated after intravenous administration of (99m)Tc-liposomal doxorubicin. SPECT/CT and planar scintigraphy were performed at the same posttreatment intervals applied in the first experiment, with additional planar imaging performed at 44 hours. After imaging, tissue counting in the excised tumors was performed. Radiotracer uptake, as determined with imaging and tissue counting, was quantified and compared. In a subset of three animals, intratumoral doxorubicin accumulation was determined with fluorimetry and correlated with the imaging and tissue-counting data. RESULTS: At both SPECT/CT and planar scintigraphy, increased uptake of (99m)Tc-liposomal doxorubicin was visibly apparent in the ablated tumors. Results of quantitative analysis with both imaging and tissue counting confirmed significantly greater uptake in the RF ablation-treated tumors (P < .001). Intratumoral doxorubicin accumulation correlated closely with imaging (r = 0.9185-0.9871) and tissue-counting (r = 0.995) results. CONCLUSION: Study results show that increased delivery of intravenous liposomal doxorubicin to tumors combined with RF ablation can be depicted and quantified with noninvasive imaging.226Ljungkvist, A. S. E.; Bussink, J.; Kaanders, J. H. A. M.; van der Kogel, A. J. Dynamics of Tumor Hypoxia Measured with Bioreductive Hypoxic Cell Markers. Radiat. Res. 2007, 167, 127– 145, DOI: 10.1667/RR0719.1[Crossref], [PubMed], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlOhs78%253D&md5=6651faff795bb0e8420f2310e9fc151cDynamics of tumor hypoxia measured with bioreductive hypoxic cell markersLjungkvist, Anna S. E.; Bussink, Johan; Kaanders, Johannes H. A. M.; van der Kogel, Albert J.Radiation Research (2007), 167 (2), 127-145CODEN: RAREAE; ISSN:0033-7587. (Radiation Research Society)A review. Hypoxic cells are common in tumors and contribute to malignant progression, distant metastasis and resistance to radiotherapy. It is well known that tumors are heterogeneous with respect to the levels and duration of hypoxia. Several strategies, including high-oxygen-content gas breathing, radiosensitizers and hypoxic cytotoxins, have been developed to overcome hypoxia-mediated radioresistance. However, with these strategies, an increased tumor control rate is often accompanied by more severe side effects. Consequently, development of assays for prediction of tumor response and early monitoring of treatment responses could reduce both over- and undertreatment, thereby avoiding unnecessary side effects. The purpose of this review is to discuss different assays for measurement of hypoxia that can be used to detect changes in oxygen tension. The main focus is on exogenous bioreductive hypoxia markers (2-nitroimidazoles) such as pimonidazole, CCI-103F, EF5 and F-misonidazole. These are specifically reduced and bind to macromols. in viable hypoxic cells. A no. of these bioreductive drugs are approved for clin. use and can be detected with methods ranging from noninvasive PET imaging (low resoln.) to microscopic imaging of tumor sections (high resoln.). If the latter are stained for multiple markers, hypoxia can be analyzed in relation to different microenvironmental parameters such as vasculature, proliferation and endogenous hypoxia-related markers, for instance HIF1α and CA-IX. In addn., temporal and spatial changes in hypoxia can be analyzed by consecutive injection of two different hypoxia markers. Therefore, bioreductive exogenous hypoxia markers are promising as tools for development of predictive assays or as tools for early treatment monitoring and validation of potential endogenous hypoxia markers.227Vaupel, P.; Mayer, A. Hypoxia in Cancer: Significance and Impact on Clinical Outcome. Cancer Metastasis Rev. 2007, 26, 225– 239, DOI: 10.1007/s10555-007-9055-1[Crossref], [PubMed], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXotFWrtLo%253D&md5=63da460ae8b28b0fd6e5b69b10e7894dHypoxia in cancer: significance and impact on clinical outcomeVaupel, Peter; Mayer, ArnulfCancer and Metastasis Reviews (2007), 26 (2), 225-239CODEN: CMRED4; ISSN:0167-7659. (Springer)A review. Hypoxia, a characteristic feature of locally advanced solid tumors, has emerged as a pivotal factor of the tumor (patho-)physiome since it can promote tumor progression and resistance to therapy. Hypoxia represents a "Janus face" in tumor biol. because (a) it is assocd. with restrained proliferation, differentiation, necrosis or apoptosis, and (b) it can also lead to the development of an aggressive phenotype. Independent of std. prognostic factors, such as tumor stage and nodal status, hypoxia has been suggested as an adverse prognostic factor for patient outcome. Studies of tumor hypoxia involving the direct assessment of the oxygenation status have suggested worse disease-free survival for patients with hypoxic cervical cancers or soft tissue sarcomas. In head & neck cancers the studies suggest that hypoxia is prognostic for survival and local control. Tech. limitations of the direct O2 sensing technique have prompted the use of surrogate markers for tumor hypoxia, such as hypoxia-related endogenous proteins (e.g., HIF-1α, GLUT-1, CA IX) or exogenous bioreductive drugs. In many-albeit not in all-studies endogenous markers showed prognostic significance for patient outcome. The prognostic relevance of exogenous markers, however, appears to be limited. Noninvasive assessment of hypoxia using imaging techniques can be achieved with PET or SPECT detection of radiolabeled tracers or with MRI techniques (e.g., BOLD). Clin. experience with these methods regarding patient prognosis is so far only limited. In the clin. studies performed up until now, the lack of standardized treatment protocols, inconsistencies of the endpoints characterizing the oxygenation status and methodol. differences (e.g., different immunohistochem. staining procedures) may compromise the power of the prognostic parameter used.228Brown, J. M. Tumor Hypoxia, Drug Resistance, and Metastases. J. Natl. Cancer Inst. 1990, 82, 338– 339, DOI: 10.1093/jnci/82.5.338[Crossref], [PubMed], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3c7ls1eqtA%253D%253D&md5=359a883d682549b19347e1e243ae9abaTumor hypoxia, drug resistance, and metastasesBrown J MJournal of the National Cancer Institute (1990), 82 (5), 338-9 ISSN:0027-8874.There is no expanded citation for this reference.229Challapalli, A.; Carroll, L.; Aboagye, E. O. Molecular Mechanisms of Hypoxia in Cancer. Clin. Transl. Imaging 2017, 5, 225– 253, DOI: 10.1007/s40336-017-0231-1[Crossref], [PubMed], [CAS], Google Scholar229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cnmsFGmsA%253D%253D&md5=13a5a815280895929fcb5900c7389309Molecular mechanisms of hypoxia in cancerChallapalli Amarnath; Carroll Laurence; Aboagye Eric OClinical and translational imaging (2017), 5 (3), 225-253 ISSN:2281-5872.PURPOSE: Hypoxia is a condition of insufficient oxygen to support metabolism which occurs when the vascular supply is interrupted, or when a tumour outgrows its vascular supply. It is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. This review provides an overview of hypoxia imaging with Positron emission tomography (PET), with an emphasis on the biological relevance, mechanism of action, highlighting advantages, and limitations of the currently available hypoxia radiotracers. METHODS: A comprehensive PubMed literature search was performed, identifying articles relating to biological significance and measurement of hypoxia, MRI methods, and PET imaging of hypoxia in preclinical and clinical settings, up to December 2016. RESULTS: A variety of approaches have been explored over the years for detecting and monitoring changes in tumour hypoxia, including regional measurements with oxygen electrodes placed under CT guidance, MRI methods that measure either oxygenation or lactate production consequent to hypoxia, different nuclear medicine approaches that utilise imaging agents the accumulation of which is inversely related to oxygen tension, and optical methods. The advantages and disadvantages of these approaches are reviewed, along with individual strategies for validating different imaging methods. PET is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. CONCLUSION: Even though hypoxia could have significant prognostic and predictive value in the clinic, the best method for hypoxia assessment has in our opinion not been realised.230Dewhirst, M. W.; Cao, Y.; Moeller, B. Cycling Hypoxia and Free Radicals Regulate Angiogenesis and Radiotherapy Response. Nat. Rev. Cancer 2008, 8, 425– 437, DOI: 10.1038/nrc2397[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmt1Oksbo%253D&md5=0274e5238dbedb494167f3c882946215Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy responseDewhirst, Mark W.; Cao, Yiting; Moeller, BenjaminNature Reviews Cancer (2008), 8 (6), 425-437CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. Hypoxia and free radicals, such as reactive oxygen and nitrogen species, alter the activity of the transcription factor HIF1, which can regulate tumor cell survival and angiogenesis. Intratumoral heterogeneity of these factors significantly affects HIF1 and consequently the response to cytotoxic therapy. Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumor development. The hypoxic environment of tumors is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumor cell survival. As discussed here, a const. theme emerges: inhibition of HIF1 activity will have therapeutic benefit.231Kushibiki, T.; Hirasawa, T.; Okawa, S.; Ishihara, M. Responses of Cancer Cells Induced by Photodynamic Therapy. J. Healthc. Eng. 2013, 4, 87– 108, DOI: 10.1260/2040-2295.4.1.87[Crossref], [PubMed], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3svnt1CmsQ%253D%253D&md5=d6724d472afa4095180791924c525840Responses of cancer cells induced by photodynamic therapyKushibiki Toshihiro; Hirasawa Takeshi; Okawa Shinpei; Ishihara MiyaJournal of healthcare engineering (2013), 4 (1), 87-108 ISSN:2040-2295.Photodynamic therapy (PDT) involves the administration of a photosensitizer, followed by local irradiation of tumor tissues using a laser of an appropriate wavelength to activate the photosensitizer. Since multiple cellular signaling cascades are concomitantly activated in cancer cells exposed to the photodynamic effect, understanding the responses of cancer cells to PDT will aid in the development of new interventions. This review describes the possible cell-death signaling pathways initiated by PDT. In addition, we describe our latest findings regarding the induction of expression of miRNAs specific to apoptosis in cancer cells and the induction of antitumor immunity following PDT against cancer cells. A more detailed understanding of the molecular mechanisms related to PDT will potentially improve long-term survival of PDT treated patients.232Li, S.; Meng, W.; Guan, Z.; Guo, Y.; Han, X. The Hypoxia-Related Signaling Pathways of Vasculogenic Mimicry in Tumor Treatment. Biomed. Pharmacother. 2016, 80, 127– 135, DOI: 10.1016/j.biopha.2016.03.010[Crossref], [PubMed], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xks1Cmsbw%253D&md5=ae56cd305bf09ab3a8e53843ad146f5dThe hypoxia-related signaling pathways of vasculogenic mimicry in tumor treatmentLi, Shuixian; Meng, Wen; Guan, Ziwei; Guo, Yuanling; Han, XiuzhenBiomedicine & Pharmacotherapy (2016), 80 (), 127-135CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)Tumors require a blood supply for survival, growth, and metastasis. It is widely accepted that the development of the tumor microcirculation compartment need the prodn. of new blood vessels (angiogenesis). Vasculogenic mimicry (VM) is an alternative type of blood supplement independent of endothelial vessels which refers to the formation of tumor cell-lined vessels and is assocd. with tumor invasion, metastasis and poor cancer patient prognosis. Although a variety of proteins and microenvironmental factors are known to contribute to VM, the mechanisms underlying its formation remain unclear. The induction of VM seems to be related to hypoxia, which may promote the plastic, transendothelial phenotype of tumor cells capable of VM. Here, with regard to the above aspects, we review the advanced research on VM including mol. mechanisms and its clin. significance; and explore the development of VM-related strategies which are being utilized for anticancer treatment.233Yao, J.; Feng, J.; Gao, X.; Wei, D.; Kang, T.; Zhu, Q.; Jiang, T.; Wei, X.; Chen, J. Neovasculature and Circulating Tumor Cells Dual-Targeting Nanoparticles for the Treatment of the Highly-Invasive Breast Cancer. Biomaterials 2017, 113, 1– 17, DOI: 10.1016/j.biomaterials.2016.10.033[Crossref], [PubMed], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslCrt7jN&md5=398d22543ae117f01e4fac99a8182684Neovasculature and circulating tumor cells dual-targeting nanoparticles for the treatment of the highly-invasive breast cancerYao, Jianhui; Feng, Jingxian; Gao, Xiaoling; Wei, Dan; Kang, Ting; Zhu, Qianqian; Jiang, Tianze; Wei, Xunbin; Chen, JunBiomaterials (2017), 113 (), 1-17CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Antiangiogenesis therapy has been served as a potent cancer treatment strategy for decades, yet disrupting neovasculature would provoke tumor cells into invasive growth and result in distal metastasis. The basic cause of cancer metastasis can be traced down to the presence of circulating tumor cells (CTCs) which detach from primary tumor site and act as 'seeds'. Epithelial cell adhesion mol. (EpCAM) is a potential biomarker for selective capture of epithelium-derived CTCs. Here, we integrated tumor neovessles-targetable ligands K237 peptide with Ep23 aptamer against EpCAM into a single drug-loaded nanoplatform using paclitaxel (PTX) as the model drug, aiming at damaging the primary tumor and neutralizing CTCs simultaneously to achieve a synergistic anti-tumor therapeutic effect. Enhanced cellular uptake, cell apoptosis-induction and cell-viability inhibition efficiency of the peptide and aptamer dual-functionalized nanoparticles (dTNP) were obsd. in both human umbilical vein endothelial cells (HUVEC) and 4T1 cells in vitro. Using cone-and-plate viscometer to create venous flow velocity, dTNP was also found to be able to capture CTCs under shear stress. The CTC-targeting and neutralization effect of dTNP in bloodstream and 4T1-GFP cell-derived lung metastasis mice model was confirmed via in vivo flow cytometry (IVFC), intravital imaging and confocal microscopy anal. As a result, the orthotropic breast tumor-bearing mice administrated with PTX-loaded dTNP exhibited the optimal therapeutic effect. Taken together, the findings here provided direct evidence that the tumor neovasculature and CTCs dual-targeting drug delivery system could provide a novel modality for the treatment of highly-invasive breast cancer.234Gray, L. H.; Conger, A. D.; Ebert, M.; Hornsey, S.; Scott, O. C. The Concentration of Oxygen Dissolved in Tissues at the Time of Irradiation as a Factor in Radiotherapy. Br. J. Radiol. 1953, 26, 638– 648, DOI: 10.1259/0007-1285-26-312-638[Crossref], [PubMed], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG2cXhvVGjsA%253D%253D&md5=499ec5b0ac6a031247047c40c040f21dThe concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapyGray, L. H.; Conger, A. D.; Ebert, M.; Hornsey, S.; Scott, O. C. A.British Journal of Radiology (1953), 26 (), 638-48CODEN: BJRAAP; ISSN:0007-1285.The sensitivity of tumor cells to x-rays is about 3 times as great when irradiated in a well-oxygenated medium as under anoxic conditions. The manner in which sensitivity depends on O2 tension closely resembles that found by other workers for plant and insect tissues. The sensitivity of the tumor cells to fast neutron radiation is only slightly affected by O2 tension. In certain circumstances the effectiveness of x-ray treatment might be increased if the patient were breathing O2 at the time of irradiation.235Mottram, J. C. A. Factor of Importance in the Radio Sensitivity of Tumours. Br. J. Radiol. 1936, 9, 606– 614, DOI: 10.1259/0007-1285-9-105-606236Arbeit, J. M.; Brown, J. M.; Chao, K. S. C.; Chapman, J. D.; Eckelman, W. C.; Fyles, A. W.; Giaccia, A. J.; Hill, R. P.; Koch, C. J.; Krishna, M. C.; Krohn, K. A.; Lewis, J. S.; Mason, R. P.; Melillo, G.; Padhani, A. R.; Powis, G.; Rajendran, J. G.; Reba, R.; Robinson, S. P.; Semenza, G. L.; Swartz, H. M.; Vaupel, P.; Yang, D.; Tatum, J. L. Hypoxia: Importance in Tumor Biology, Noninvasive Measurement by Imaging, and Value of Its Measurement in the Management of Cancer Therapy. Int. J. Radiat. Biol. 2006, 82, 699– 757, DOI: 10.1080/09553000601002324[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtlejsbnM&md5=8d1221e95c8063c845521b3652782725Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapyTatum, James L.; Kelloff, Gary J.; Gillies, Robert J.; Arbeit, Jeffrey M.; Brown, J. Martin; Chao, K. S. Clifford; Chapman, J. Donald; Eckelman, William C.; Fyles, Anthony W.; Giaccia, Amato J.; Hill, Richard P.; Koch, Cameron J.; Krishna, Murali Cherukuri; Krohn, Kenneth A.; Lewis, Jason S.; Mason, Ralph P.; Melillo, Giovanni; Padhani, Anwar R.; Powis, Garth; Rajendran, Joseph G.; Reba, Richard; Robinson, Simon P.; Semenza, Gregg L.; Swartz, Harold M.; Vaupel, Peter; Yang, David; Croft, Barbara; Hoffman, John; Liu, Guoying; Stone, Helen; Sullivan, DanielInternational Journal of Radiation Biology (2006), 82 (10), 699-757CODEN: IJRBE7; ISSN:0955-3002. (Informa Healthcare)A review. Purpose: The Cancer Imaging Program of the National Cancer Institute convened a workshop to assess the current status of hypoxia imaging, to assess what is known about the biol. of hypoxia as it relates to cancer and cancer therapy, and to define clin. scenarios in which in vivo hypoxia imaging could prove valuable. Results: Hypoxia, or low oxygenation, has emerged as an important factor in tumor biol. and response to cancer treatment. It has been correlated with angiogenesis, tumor aggressiveness, local recurrence, and metastasis, and it appears to be a prognostic factor for several cancers, including those of the cervix, head and neck, prostate, pancreas, and brain. The relationship between tumor oxygenation and response to radiation therapy has been well established, but hypoxia also affects and is affected by some chemotherapeutic agents. Although hypoxia is an important aspect of tumor physiol. and response to treatment, the lack of simple and efficient methods to measure and image oxygenation hampers further understanding and limits their prognostic usefulness. There is no gold std. for measuring hypoxia; Eppendorf measurement of pO2 has been used, but this method is invasive. Recent studies have focused on mol. markers of hypoxia, such as hypoxia inducible factor 1 (HIF-1) and carbonic anhydrase isoenzyme IX (CA-IX), and on developing noninvasive imaging techniques. Conclusions: This workshop yielded recommendations on using hypoxia measurement to identify patients who would respond best to radiation therapy, which would improve treatment planning. This represents a narrow focus, as hypoxia measurement might also prove useful in drug development and in increasing our understanding of tumor biol.237Chapman, J. D.; Franko, A. J.; Sharplin, J. A Marker for Hypoxic Cells in Tumours with Potential Clinical Applicability. Br. J. Cancer 1981, 43, 546– 550, DOI: 10.1038/bjc.1981.79[Crossref], [PubMed], [CAS], Google Scholar237https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXkslKgtLs%253D&md5=f95456131173e62668ec8a3003e634bcA marker for hypoxic cells in tumors with potential clinical applicabilityChapman, J. D.; Franko, A. J.; Sharplin, J.British Journal of Cancer (1981), 43 (4), 546-50CODEN: BJCAAI; ISSN:0007-0920.Autoradiog. studies in multicellular spheroids of Chinese hamster V79 cells and EMT-6 fibrosarcomas following incubation with 50 μM misonidazole-14C (I) for 3 h at 37° indicated that I may be a marker for viable hypoxic cells at concns. not expected to produce radiosensitization or cytotoxicity.238Gallez, B.; Baudelet, C.; Jordan, B. F. Assessment of Tumor Oxygenation by Electron Paramagnetic Resonance: Principles and Applications. NMR Biomed. 2004, 17, 240– 262, DOI: 10.1002/nbm.900[Crossref], [PubMed], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXptFSmsL0%253D&md5=08f48eebabc97de39398ac458dc0fdf1Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applicationsGallez, Bernard; Baudelet, Christine; Jordan, Benedicte F.NMR in Biomedicine (2004), 17 (5), 240-262CODEN: NMRBEF; ISSN:0952-3480. (John Wiley & Sons Ltd.)This review paper attempts to provide an overview of the principles and techniques that are often termed ESR (EPR) oximetry. The paper discusses the potential of such methods and illustrates they have been successfully applied to measure oxygen tension, an essential parameter of the tumor microenvironment. To help the reader understand the motivation for carrying out these measurements, the importance of tumor hypoxia is first discussed: the basic issues of why a tumor is hypoxic, why these hypoxic microenvironments promote processes driving malignant progression and why hypoxia dramatically influences the response of tumors to cytotoxic treatments will be explained. The different methods that have been used to est. the oxygenation in tumors will be reviewed. To introduce the basics of EPR oximetry, the specificity of in vivo EPR will be discussed by comparing this technique with NMR and MRI. The different types of paramagnetic oxygen sensors will be presented, as well as the methods for recording the information (EPR spectroscopy, EPR imaging, dynamic nuclear polarization). Several applications of EPR for characterizing tumor oxygenation will be illustrated, with a special emphasis on pharmacol. interventions that modulate the tumor microenvironment. Finally, the challenges for transposing the method into the clinic will also be discussed.239Kwock, L.; Gill, M.; McMurry, H. L.; Beckman, W.; Raleigh, J. A.; Joseph, A. P. Evaluation of a Fluorinated 2-Nitroimidazole Binding to Hypoxic Cells in Tumor-Bearing Rats by 19F Magnetic Resonance Spectroscopy and Immunohistochemistry. Radiat. Res. 1992, 129, 71, DOI: 10.2307/3577905[Crossref], [PubMed], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XhtVWqsr0%253D&md5=c72a8775ca54ab264e75e1660e1d8d2eEvaluation of a fluorinated 2-nitroimidazole binding to hypoxic cells in tumor-bearing rats by fluorine-19 magnetic resonance spectroscopy and immunohistochemistryKwock, Lester; Gill, Michael; McMurray, Harris L.; Beckman, William; Raleigh, James A.; Joseph, Andrew P.Radiation Research (1992), 129 (1), 71-8CODEN: RAREAE; ISSN:0033-7587.A hexafluorinated 2-nitroimidazole, CCI-103F, was evaluated as a probe for hypoxic tumor cells by in vivo 19F magnetic resonance spectroscopy (MRS). Following initial i.p. injections of the drug in tumor-bearing (Dunning R3327-AT1-Matlylu) rats, 19F spectra were obtained on an Otsuka 2.0T Vivospec spectrometer using a 1.5-cm surface coil. The signal at 1- and 2-h time points indicated initial biodistribution of drug in the tumor. At 4 and 8 h, a progressive increase in signal intensity was obsd., indicating retention of drug within the tumor. Tumor signal remained detectable in 4 of 10 rats at 24 h, indicating possible nitroreductive bioactivation by hypoxic cells. Immunohistochem. of these tumors revealed a staining pattern consistent with labeling of hypoxic cells. No detectable 19F signal was found at 24 h for the other rats, indicating complete washout of unbound drug. Immunohistochem. assessment of these tumors revealed some staining for bound drug at the periphery of necrotic zones. 31P-MRS of the tumors showed good correlation with the presence or absence of hypoxia as evaluated by 19F-MRS, T1- and T2-weighted images, and immunohistochem. These results provide the groundwork for further studies using this misonidazole analog for noninvasive identification of hypoxic tumor cells in vivo by MRS.240Dunn, J. F.; O’Hara, J. A.; Zaim-Wadghiri, Y.; Lei, H.; Meyerand, M. E.; Grinberg, O. Y.; Hou, H.; Hoopes, P. J.; Demidenko, E.; Swartz, H. M. Changes in Oxygenation of Intracranial Tumors With Carbogen: A BOLD MRI and EPR Oximetry Study. J. Magn. Reson. Imaging 2002, 16, 511– 521, DOI: 10.1002/jmri.10192[Crossref], [PubMed], [CAS], Google Scholar240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD38nltlSjuw%253D%253D&md5=cff9bd37a779703af0c998c01c344a89Changes in oxygenation of intracranial tumors with carbogen: a BOLD MRI and EPR oximetry studyDunn Jeff F; O'Hara Julia A; Zaim-Wadghiri Youssef; Lei Hao; Meyerand M Elizabeth; Grinberg Oleg Y; Hou Huagang; Hoopes P Jack; Demidenko Eugene; Swartz Harold MJournal of magnetic resonance imaging : JMRI (2002), 16 (5), 511-21 ISSN:1053-1807.PURPOSE: To examine, using blood oxygen level dependent (BOLD) MRI and EPR oximetry, the changes in oxygenation of intracranial tumors induced by carbogen breathing. MATERIALS AND METHODS: The 9L and CNS-1 intracranial rat tumor models were imaged at 7T, before and during carbogen breathing, using a multi-echo gradient-echo (GE) sequence to map R(2)*. On a different group of 9L tumors, tissue pO(2) was measured using EPR oximetry with lithium phthalocyanine as the oxygen-sensitive material. RESULTS: The average decline in R(2)* with carbogen breathing was 13 +/- 1 s(-1) in the CNS-1 tumors and 29 +/- 4 s(-1) in the 9L tumor. The SI vs. TE decay curves indicate the presence of multiple components in the tumor. Tissue pO(2) in the two 9L tumors measured was 8.6 +/- 0.5 and 3.6 +/- 0.6 mmHg during air breathing, and rose to 20 +/- 7 and 16 +/- 4 mmHg (mean +/- SE) with carbogen breathing. Significant changes were observed by 10 minutes, but changes in pO(2) and R(2)* continued in some subjects over the entire 40 minutes. CONCLUSION: EPR results indicate that glial sarcomas may be radiobiologically hypoxic. Both EPR and BOLD data indicate that carbogen breathing increases brain tumor oxygenation. These data support the use of BOLD imaging to monitor changes in oxygenation in brain tumors.241Landuyt, W.; Hermans, R.; Bosmans, H.; Sunaert, S.; Beatse, E.; Farina, D.; Meijerink, M.; Zhang, H.; Bogaert, W.; Lambin, P.; Marchal, G. BOLD Contrast FMRI of Whole Rodent Tumour During Air or Carbogen Breathing Using Echo-Planar Imaging at 1.5 T. Eur. Radiol. 2001, 11, 2332– 2340, DOI: 10.1007/s003300100996[Crossref], [PubMed], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3MnkvVygsQ%253D%253D&md5=89037d859c0b16c02e7a3f3eb1ae396fBOLD contrast fMRI of whole rodent tumour during air or carbogen breathing using echo-planar imaging at 1.5 TLanduyt W; Hermans R; Bosmans H; Sunaert S; Beatse E; Farina D; Meijerink M; Zhang H; Van Den Bogaert W; Lambin P; Marchal GEuropean radiology (2001), 11 (11), 2332-40 ISSN:0938-7994.The aim of this study was to evaluate the feasibility of functional MR imaging (fMRI) at 1.5 T, exploiting blood oxygenation level-dependent (BOLD) contrast, for detecting changes in whole-tumour oxygenation induced by carbogen (5% CO2+95% O2) inhalation of the host. Adult WAG/Rij rats with rhabdomyosarcomas growing subcutaneously in the lower flank were imaged when tumours reached sizes between 1 and 11 cm3 (n=12). Air and carbogen were alternatively supplied at 2 l/min using a snout mask. Imaging was done on a 1.5-T MR scanner using a T2*-weighted gradient-echo, echo-planar imaging (GE-EPI) sequence. Analysis of the whole-tumour EPI images was based on statistical parametric maps. Voxels with and without signal intensity changes (SIC) were recorded. Significance thresholds were set at p<0.05, corrected for multiple comparisons. In continuous air breathing condition, 3 of 12 tumours showed significant negative SIC and 1 tumour had a clear-cut positive SIC. The remaining tumours showed very little or no change. When switching to carbogen breathing, the SIC were significantly positive in 10 of 12 tumours. Negative SIC were present in 4 tumours, of which three were simultaneously characterised by positive SIC. The overall analysis indicated that 6 of the 12 tumours could be considered as strong positive responders to carbogen. Our research demonstrates the applicability of fMRI GE-EPI at 1.5 T to study whole-tumour oxygenation non-invasively. The observed negative SIC during air condition may reflect the presence of transient hypoxia during these measurements. Selection of tumours on the basis of their individual response to carbogen is possible, indicating a role of such non-invasive measurements for using tailor-made treatments.242Kelada, O. J.; Carlson, D. J. Molecular Imaging of Tumor Hypoxia with Positron Emission Tomography. Radiat. Res. 2014, 181, 335– 349, DOI: 10.1667/RR13590.1[Crossref], [PubMed], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXot12isrw%253D&md5=8b8384fd55777b705a392dcf54ea1533Molecular imaging of tumor hypoxia with positron emission tomographyKelada, Olivia J.; Carlson, David J.Radiation Research (2014), 181 (4), 335-349CODEN: RAREAE; ISSN:0033-7587. (Radiation Research Society)A review. The problem of tumor hypoxia has been recognized and studied by the oncol. community for over 60 years. From radiation and chemotherapy resistance to the increased risk of metastasis, low oxygen concns. in tumors have caused patients with many types of tumors to respond poorly to conventional cancer therapies. It is clear that patients with high levels of tumor hypoxia have a poorer overall treatment response and that the magnitude of hypoxia is an important prognostic factor. As a result, the development of methods to measure tumor hypoxia using invasive and noninvasive techniques has become desirable to the clin. oncol. community. A variety of imaging modalities have been established to visualize hypoxia in vivo. Positron emission tomog. (PET) imaging, in particular, has played a key role for imaging tumor hypoxia because of the development of hypoxia-specific radiolabeled agents. Consequently, this technique is increasingly used in the clinic for a wide variety of cancer types. Following a broad overview of the complexity of tumor hypoxia and measurement techniques to date, this article will focus specifically on the accuracy and reproducibility of PET imaging to quantify tumor hypoxia. Despite numerous advances in the field of PET imaging for hypoxia, we continue to search for the ideal hypoxia tracer to both qual. and quant. define the tumor hypoxic vol. in a clin. setting to optimize treatments and predict response in cancer patients.243Vaupel, P. Tumor Microenvironmental Physiology and Its Implications for Radiation Oncology. Semin. Radiat. Oncol. 2004, 14, 198– 206, DOI: 10.1016/j.semradonc.2004.04.008[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2czltFOrsQ%253D%253D&md5=52dc30f316eac2b99d237f3e2ddbe064Tumor microenvironmental physiology and its implications for radiation oncologyVaupel PeterSeminars in radiation oncology (2004), 14 (3), 198-206 ISSN:1053-4296.The microenvironmental physiology of tumors is uniquely different from that of normal tissues. It is characterized, inter alia, by O(2) depletion (hypoxia, anoxia), glucose and energy deprivation, high lactate levels, and extracellular acidosis, parameters that are anisotropically distributed within the tumor mass. This hostile microenvironment is largely dictated by the abnormal tumor vasculature and heterogeneous microcirculation. Hypoxia and other hostile microenvironmental parameters are known to directly or indirectly confer resistance to irradiation leading to treatment failure. Hypoxia directly leads to a reduced "fixation" of radiation-induced DNA damage. Indirect mechanisms include a restrained proliferation, changes in gene expression and alterations of the proteome (eg, elevated activity of DNA-repair enzymes and resistance-related proteins, increased transcription of growth factors), and genomic changes (genomic instability leading to clonal heterogeneity and selection of resistant clonal variants). These changes, caused by the hostile microenvironment, can favor tumor progression and acquired treatment resistance, both resulting in poor clinical outcome and prognosis. Pretreatment assessment of critical microenvironmental parameters is therefore needed to allow the selection of patients who could benefit from special treatment approaches (eg, hypoxia-targeting therapy). Because of a relatively high risk of local relapse or distant metastasis, patients with hypoxic and/or "high-lactate" tumors should undergo close surveillance.244Mees, G.; Dierckx, R.; Vangestel, C.; Van De Wiele, C. Molecular Imaging of Hypoxia with Radiolabelled Agents. Eur. J. Nucl. Med. Mol. Imaging 2009, 36, 1674– 1686, DOI: 10.1007/s00259-009-1195-9[Crossref], [PubMed], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1WhtLrI&md5=7784884b9f04349674a573fd78897e80Molecular imaging of hypoxia with radiolabelled agentsMees, Gilles; Dierckx, Rudi; Vangestel, Christel; Van de Wiele, ChristopheEuropean Journal of Nuclear Medicine and Molecular Imaging (2009), 36 (10), 1674-1686CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. Tissue hypoxia results from an inadequate supply of oxygen (O2) that compromises biol. functions. Structural and functional abnormalities of the tumor vasculature together with altered diffusion conditions inside the tumor seem to be the main causes of tumor hypoxia. Evidence from exptl. and clin. studies points to a role for tumor hypoxia in tumor propagation, resistance to therapy and malignant progression. This has led to the development of assays for the detection of hypoxia in patients in order to predict outcome and identify patients with a worse prognosis and/or patients that would benefit from appropriate treatments. A variety of invasive and non-invasive approaches have been developed to measure tumor oxygenation including oxygen-sensitive electrodes and hypoxia marker techniques using various labels that can be detected by different methods such as positron emission tomog. (PET), single photon emission computed tomog. (SPECT), magnetic resonance imaging (MRI), autoradiog. and immunohistochem. This review aims to give a detailed overview of non-invasive mol. imaging modalities with radiolabeled PET and SPECT tracers that are available to measure tumor hypoxia.245Lee, S. T.; Scott, A. M. Hypoxia Positron Emission Tomography Imaging With 18F-Fluoromisonidazole. Semin. Nucl. Med. 2007, 37, 451– 461, DOI: 10.1053/j.semnuclmed.2007.07.001[Crossref], [PubMed], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2srpvFClsw%253D%253D&md5=24137699a9739ab35d0758bdd2c87676Hypoxia positron emission tomography imaging with 18f-fluoromisonidazoleLee Sze Ting; Scott Andrew MSeminars in nuclear medicine (2007), 37 (6), 451-61 ISSN:0001-2998.The importance of hypoxia in disease pathogenesis and prognosis is gathering increasing clinical significance and having a greater impact on patient management and outcome. Previous efforts to evaluate hypoxia have included the invasive assessment of hypoxia with immunohistologic and histographic oxygen probes. The emergence of new radiotracers has allowed noninvasive assessment of hypoxia, with the most extensively investigated and validated positron emission tomography radiotracer of hypoxia to date being (18)F-fluoromisonodazole ((18)F-FMISO). This review discusses the relevance and biology of hypoxia in cells and organ systems, and reviews the laboratory and clinical applications of (18)F-FMISO in oncology and noncancer disease states.246Koh, W. J.; Griffin, T. W.; Rasfy, J. S.; Laramore, G. E. Positron Emission Tomography: A New Tool for Characterization of Malignant Disease and Selection of Therapy. Acta Oncol. 1994, 33, 323– 327, DOI: 10.3109/02841869409098424[Crossref], [PubMed], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2c3ovFSgug%253D%253D&md5=1ef63a90dc4b9f55056438af27c24224Positron emission tomography. A new tool for characterization of malignant disease and selection of therapyKoh W J; Griffin T W; Rasey J S; Laramore G EActa oncologica (Stockholm, Sweden) (1994), 33 (3), 323-7 ISSN:0284-186X.Present therapy for cancer patients is based primarily on tumor histology and anatomy. Despite treatment advances, clinicians have often been frustrated by their inability to assess tumor biology. Metabolic imaging by positron emission tomography is a promising new technology that has opened up a whole realm of study in oncology. Glucose metabolism, hemodynamics, oxygen utilization, protein synthesis and thymidine incorporation may yield valuable data regarding tumor aggressiveness and stage, and allow assessment of tumor response early during treatment, before morphological changes are detectable. Other metabolic determinations, including tumor hypoxia and estrogen receptor density, may predict tumor response to therapy, and lead to selection of more appropriate treatment regimens, such as with neutrons or hypoxic cell sensitizers for documentably hypoxic tumors. While further clinical validation is required, positron emission tomography promises to provide vital information complementary to present anatomical imaging modalities that will aid oncologists in optimal management of their patients.247Cortezon-Tamarit, F.; Sarpaki, S.; Calatayud, D. G.; Mirabello, V.; Pascu, S. I. Applications of “Hot” and “Cold” Bis(Thiosemicarbazonato) Metal Complexes in Multimodal Imaging. Chem. Rec. 2016, 16, 1380– 1397, DOI: 10.1002/tcr.201500292[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnsVyrsbk%253D&md5=541f7091360f4fc811271b380ed1c2b4Applications of "Hot" and "Cold" Bis(thiosemicarbazonato) Metal Complexes in Multimodal ImagingCortezon-Tamarit, Fernando; Sarpaki, Sophia; Calatayud, David G.; Mirabello, Vincenzo; Pascu, Sofia I.Chemical Record (2016), 16 (3), 1380-1397CODEN: CRHEAK; ISSN:1528-0691. (Wiley-VCH Verlag GmbH & Co. KGaA)The applications of coordination chem. to mol. imaging has become a matter of intense research over the past 10 years. In particular, the applications of bis(thiosemicarbazonato) metal complexes in mol. imaging have mainly been focused on compds. with aliph. backbones due to the in vivo imaging success of hypoxic tumors with PET (positron emission tomog.) using 64CuATSM [copper (diacetyl-bis(N4-methylthiosemicarbazone))]. This compd. entered clin. trials in the US and the UK during the first decade of the 21st century for imaging hypoxia in head and neck tumors. The replacement of the ligand backbone to arom. groups, coupled with the exocyclic N's functionalization during the synthesis of bis(thiosemicarbazones) opens the possibility to use the corresponding metal complexes as multimodal imaging agents of use, both in vitro for optical detection, and in vivo when radiolabeled with several different metallic species. The greater kinetic stability of acenaphthenequinone bis(thiosemicarbazonato) metal complexes, with respect to that of the corresponding aliph. ATSM complexes, allows the stabilization of a no. of imaging probes, with special interest in "cold" and "hot" Cu(II) and Ga(III) derivs. for PET applications and 111In(III) derivs. for SPECT (single-photon emission computed tomog.) applications, while Zn(II) derivs. display optical imaging properties in cells, with enhanced fluorescence emission and lifetime with respect to the free ligands. Preliminary studies have shown that gallium-based acenaphthenequinone bis(thiosemicarbazonato) complexes are also hypoxia selective in vitro, thus increasing the interest in them as new generation imaging agents for in vitro and in vivo applications.248Hueting, R.; Kersemans, V.; Cornelissen, B.; Tredwell, M.; Hussien, K.; Christlieb, M.; Gee, A. D.; Passchier, J.; Smart, S. C.; Dilworth, J. R.; Gouverneur, V.; Muschel, R. J. A Comparison of the Behavior of 64Cu-Acetate and 64Cu-ATSM in Vitro and in Vivo. J. Nucl. Med. 2014, 55, 128– 134, DOI: 10.2967/jnumed.113.119917[Crossref], [PubMed], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjtlCkurs%253D&md5=36ec03664adc886abb76d2884ca36b51A comparison of the behavior of 64Cu-acetate and 64Cu-ATSM in vitro and in vivoHueting, Rebekka; Kersemans, Veerle; Cornelissen, Bart; Tredwell, Matthew; Hussein, Kamila; Christlieb, Martin; Gee, Antony D.; Passchier, Jan; Smart, Sean C.; Dilworth, Jonathan R.; Gouverneur, Veronique; Muschel, Ruth J.Journal of Nuclear Medicine (2014), 55 (1), 128-134CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)64Cu-diacetyl-bis(N4-methylthiosemicarbazonate), 64Cu-ATSM, continues to be investigated clin. as a PET agent both for delineation of tumor hypoxia and as an effective indicator of patient prognosis, but there are still aspects of the mechanism of action that are not fully understood. Methods: The retention of radioactivity in tumors after administration of 64Cu-ATSM in vivo is substantially higher for tumors with a significant hypoxic fraction. This hypoxia-dependent retention is believed to involve the redn. of Cu-ATSM, followed by the loss of copper to cellular copper processing. To shed light on a possible role of copper metab. in hypoxia targeting, we have compared 64Cu retention in vitro and in vivo in CaNT and EMT6 cells or cancers after the administration of 64Cu-ATSM or 64Cu-acetate. Results: In vivo in mice bearing CaNT or EMT6 tumors, biodistributions and dynamic PET data are broadly similar for 64Cu-ATSM and 64Cu-acetate. Copper retention in tumors at 15 min is higher after injection of 64Cu-acetate than 64Cu-ATSM, but similar values result at 2 and 16 h for both. Colocalization with hypoxia as measured by EF5 immunohistochem. is evident for both at 16 h after administration but not at 15 min or 2 h. Interestingly, at 2 h tumor retention for 64Cu-acetate and 64Cu-ATSM, although not colocalizing with hypoxia, is reduced by similar amts. by increased tumor oxygenation due to inhalation of increased O2. In vitro, substantially less uptake is obsd. for 64Cu-acetate, although this uptake had some hypoxia selectivity. Although 64Cu-ATSM is stable in mouse serum alone, there is rapid disappearance of intact complex from the blood in vivo and comparable amts. of serum bound activity for both 64Cu-ATSM and 64Cu-acetate. Conclusion: That in vivo, in the EMT6 and CaNT tumors studied, the distribution of radiocopper from 64Cu-ATSM in tumors essentially mirrors that of 64Cu-acetate suggests that copper metab. may also play a role in the mechanism of selectivity of Cu-ATSM.249Holland, J. P.; Aigbirhio, F. I.; Betts, H. M.; Bonnitcha, P. D.; Burke, P.; Christlieb, M.; Churchill, G. C.; Cowley, A. R.; Dilworth, J. R.; Donnelly, P. S.; Green, J. C.; Peach, J. M.; Vasudevan, S. R.; Warren, J. E. Functionalized Bis(Thiosemicarbazonato) Complexes of Zinc and Copper: Synthetic Platforms Toward Site-Specific Radiopharmaceuticals. Inorg. Chem. 2007, 46, 465– 485, DOI: 10.1021/ic0615628[ACS Full Text], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xhtlekt7rP&md5=b01bd55817ee45019eada793fa571dffFunctionalized Bis(thiosemicarbazonato) Complexes of Zinc and Copper: Synthetic Platforms Toward Site-Specific RadiopharmaceuticalsHolland, Jason P.; Aigbirhio, Franklin I.; Betts, Helen M.; Bonnitcha, Paul D.; Burke, Paul; Christlieb, Martin; Churchill, Grant C.; Cowley, Andrew R.; Dilworth, Jonathan R.; Donnelly, Paul S.; Green, Jennifer C.; Peach, Josephine M.; Vasudevan, Sridhar R.; Warren, John E.Inorganic Chemistry (2007), 46 (2), 465-485CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)Two new types of unsym. bis(thiosemicarbazone) pro-ligands H2L (H2L = I; R3 = Me, E t, Ph, allyl; R4 = NH2, Me, Et) and their neutral zinc and copper complexes ML (M = Zn(II), Cu(II)) have been synthesized. These bifunctional ligands both chelate the metal ions and provide pendant amino groups that can be readily functionalized with biol. active mols. Functionalization has been demonstrated by the synthesis of three water-sol. glucose conjugates of the new zinc(II) bis(thiosemicarbazonato) complexes and their copper(II) analogs have been prepd. in aq. soln. via transmetalation. A range of techniques including NMR, ESR, cyclic voltammetry, high-performance liq. chromatog. (HPLC), UV/vis, and fluorescence emission spectroscopy have been used to characterize the complexes. Four compds. including two zinc(II) complexes have been characterized by X-ray crystallog. The connectivity and conformation of the glucose conjugates have been assigned by NMR spectroscopy. Time-dependent d. functional theory calcns. have been used to assign the electronic transitions of the copper(II) bis(thiosemicarbazonato) chromophore. Two copper-64-radiolabeled complexes including one glucose conjugate have been prepd. and characterized using radio-HPLC and transmetalation is shown to be a viable method for radiolabeling compds. with copper radionuclides. Preliminary cell washout studies have been performed under normoxic conditions and the uptake and intracellular distribution have been studied using confocal fluorescence microscopy.250Fujibayashi, Y.; Taniuchi, H.; Yonekura, Y.; Ohtani, H.; Konishi, J.; Yokoyama, A. Copper-62-ATSM: A New Hypoxia Imaging Agent with High Membrane Permeability and Low Redox Potential. J. Nucl. Med. 1997, 38, 1155– 1160[PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXltFChsL8%253D&md5=343ec3b3b0a1a6e886ddb85bac406496Copper-62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox potentialFujibayashi, Yasuhisa; Taniuchi, Hideyuki; Yonekura, Yoshiharu; Ohtani, Hiroshi; Konishi, Junji; Yokoyama, AkiraJournal of Nuclear Medicine (1997), 38 (7), 1155-1160CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)An ideal hypoxia imaging agent should have high membrane permeability for easy access to intracellular mitochondria and low redox potential to confer stability in normal tissue, but it should be able to be reduced by mitochondria with abnormally high electron concns. in hypoxic cells. In this context, nitroimidazole residues are not considered to be essential. In this study, Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM), a 62Cu-bisthiosemicarbazone complex, with high membrane permeability and low redox potential, was evaluated as a possible hypoxia imaging agent, using ESR spectrometry and the Langendorff isolated perfused rat heart model as well as rat heart left anterior descending occlusion model. Nonradioactive Cu-ATSM was incubated with rat mitochondria, after which redn. of Cu(II) to Cu(I) was measured with ESR. As a model of hypoxic mitochondria, rotenone (Complex I inhibitor)-treated mitochondria were used. In this study, Cu-ATSM was reduced by hypoxic but not by normal mitochondria. Thus, retention of 62Cu-ATSM was studied serially in perfused rat hearts under conditions of normoxia (95% O2 + 5% CO2), hypoxia (95% N2 + 5% CO2) and reoxygenation (95% O2 + 5% CO2). In normoxia and reoxygenation, 62Cu-ATSM injected as a single bolus showed low retention (23.77% and 22.80%, resp.) 15 min after injection, but retention was increased markedly under hypoxic conditions (81.10%). Also, in the in vivo left anterior descending occluded rat heart model, 62Cu-ATSM retention was inversely correlated with accumulation of 201Tl, a relative myocardial blood flow marker.251Sarpaki, S.; Cortezon-Tamarit, F.; De Aguiar, S. R. M. M.; Exner, R. M.; Divall, D.; Arrowsmith, R. L.; Ge, H.; Palomares, F. J.; Carroll, L.; Calatayud, D. G.; Paisey, S. J.; Aboagye, E. O.; Pascu, S. I. Radio- and Nano-Chemistry of Aqueous Ga(III) Ions Anchored onto Graphene Oxide-Modified Complexes. Nanoscale 2020, 12, 6603– 6608, DOI: 10.1039/C9NR10145D[Crossref], [PubMed], [CAS], Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXltVSgsrg%253D&md5=7a6e718a978284508be58b44bd4e0425Radio- and nano-chemistry of aqueous Ga(III) ions anchored onto graphene oxide-modified complexesSarpaki, S.; Cortezon-Tamarit, F.; de Aguiar, S. R. M. M.; Exner, R. M.; Divall, D.; Arrowsmith, R. L.; Ge, H.; Palomares, F. J.; Carroll, L.; Calatayud, D. G.; Paisey, S. J.; Aboagye, E. O.; Pascu, S. I.Nanoscale (2020), 12 (12), 6603-6608CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)The gallium-68 radiolabelling of new functional graphene oxide composites is reported herein along with kinetic stability investigations of the radio-nanohybrids under different environments and insights into their surface characteristics by SEM and XPS. The present work highlights the potential of graphene oxides as nanocarriers for small mols. such as bis(thiosemicarbazonato) complexes to act as multifunctional platforms for rapid and effective radioimaging agent incorporation.252Alam, I.; Arrowsmith, R.; Cortezon-Tamarit, F.; Tyman, F.; Kociok-Köhn, G.; Botchway, S.; Dilworth, J.; Carroll, L.; Aboagye, E.; Pascu, S. Microwave Gallium-68 Radiochemistry for Kinetically Stable Bis(Thiosemicarbazone) Complexes: Structural Investigations and Cellular Uptake Under Hypoxia. Dalt. Trans. 2016, 45, 144– 155, DOI: 10.1039/C5DT02537K253Mirabello, V.; Cortezon-Tamarit, F.; Pascu, S. I. Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-Communicable Diseases. Front. Chem. 2018, 6, 27, DOI: 10.3389/fchem.2018.00027[Crossref], [PubMed], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1egsbrP&md5=674669520202c95b0b06b2e5de7c9950Oxygen sensing, hypoxia tracing and in vivo Imaging with functional metalloprobes for the early detection of non-communicable diseasesMirabello, Vincenzo; Cortezon-Tamarit, Fernando; Pascu, Sofia I.Frontiers in Chemistry (Lausanne, Switzerland) (2018), 6 (), 27/1-27/27CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)A review. Hypoxia has been identified as one of the hallmarks of tumor environments and a prognosis factor in many cancers. The development of ideal chem. probes for imaging and sensing of hypoxia remains elusive. Crucial characteristics would include a measurable response to subtle variations of pO2 in living systems and an ability to accumulate only in the areas of interest (e.g., targeting hypoxia tissues) while exhibiting kinetic stabilities in vitro and in vivo. A sensitive probe would comprise platforms for applications in imaging and therapy for non-communicable diseases (NCDs) relying on sensitive detection of pO2. Just a handful of probes for the in vivo imaging of hypoxia [mainly using positron emission tomog. (PET)] have reached the clin. research stage. Many chem. compds., while presenting promising in vitro results as oxygen-sensing probes, are facing considerable disadvantages regarding their general application in vivo. The mechanisms of action of many hypoxia tracers have not been entirely rationalized, esp. in the case of metallo-probes. An insight into the hypoxia selectivity mechanisms can allow an optimization of current imaging probes candidates and this will be explored hereby. The mechanistic understanding of the modes of action of coordination compds. under oxygen concn. gradients in living cells allows an expansion of the scope of compds. toward in vivo applications which, in turn, would help translate these into clin. applications. We summarize hereby some of the recent research efforts made toward the discovery of new oxygen sensing mols. having a metal-ligand core. We discuss their applications in vitro and/or in vivo, with an appreciation of a plethora of mol. imaging techniques (mainly reliant on nuclear medicine techniques) currently applied in the detection and tracing of hypoxia in the preclin. and clin. setups. The design of imaging/sensing probe for early-stage diagnosis would longer term avoid invasive procedures providing platforms for therapy monitoring in a variety of NCDs and, particularly, in cancers.254Schwartz, J.; Grkovski, M.; Rimner, A.; Schöder, H.; Zanzonico, P. B.; Carlin, S. D.; Staton, K. D.; Humm, J. L.; Nehmeh, S. A. Pharmacokinetic Analysis of Dynamic 18F-Fluoromisonidazole Pet Data in Non-Small Cell Lung Cancer. J. Nucl. Med. 2017, 58, 911– 919, DOI: 10.2967/jnumed.116.180422[Crossref], [PubMed], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVagsLnL&md5=e80855f0d9d8ae1dfb2bfb5c36834b9ePharmacokinetic analysis of dynamic 18F-fluoromisonidazole PET data in non-small cell lung cancerSchwartz, Jazmin; Grkovski, Milan; Rimner, Andreas; Schoder, Heiko; Zanzonico, Pat B.; Carlin, Sean D.; Staton, Kevin D.; Humm, John L.; Nehmeh, Sadek A.Journal of Nuclear Medicine (2017), 58 (6), 911-919CODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)Hypoxic tumors exhibit increased resistance to radiation, chem., and immune therapies. 18F-fluoromisonidazole (18F-FMISO) PET is a noninvasive, quant. imaging technique used to evaluate the magnitude and spatial distribution of tumor hypoxia. In this study, pharmacokinetic anal. (PKA) of 18F-FMISO dynamic PET extended to 3 h after injection is reported for the first time, to our knowledge, in stage III-IV non-small cell lung cancer (NSCLC) patients. Methods: Sixteen patients diagnosed with NSCLC underwent 2 PET/CT scans (1-3 d apart) before radiation therapy: a 3-min static 18F-FDG and a dynamic 18F-FMISO scan lasting 168 6 15 min. The latter data were acquired in 3 serial PET/CT dynamic imaging sessions, registered with each other and analyzed using pharmacokinetic modeling software. PKA was performed using a 2-tissue, 3-compartment irreversible model, and kinetic parameters were estd. for the vols. of interest detd. using coregistered 18F-FDG images for both the vol. of interest-averaged and the voxelwise time-activity curves for each patient's lesions, normal lung, and muscle. Results: We derived av. values of 18F-FMISO kinetic parameters for NSCLC lesions as well as for normal lung and muscle. We also investigated the correlation between the trapping rate (k3) and delivery rate (K1), influx rate (Ki) consts., and tissue-to-blood activity concn. ratios (TBRs) for all tissues. Lesions had trapping rates 1.6 times larger, on av., than those of normal lung and 4.4 times larger than those in muscle. Addnl., for almost all cases, k3 and Ki had a significant strong correlation for all tissue types. The TBR-k3 correlation was less straightforward, showing a moderate to strong correlation for only 41% of lesions. Finally, K1-k3 voxelwise correlations for tumors were varied, but neg. for 76% of lesions, globally exhibiting a weak inverse relationship (av. R520.23 6 0.39). However, both normal tissue types exhibited significant pos. correlations for more than 60% of patients, with 41% having moderate to strong correlations (R. 0.5). Conclusion: All lesions showed distinct 18F-FMISO uptake. Variable 18F-FMISO delivery was obsd. across lesions, as indicated by the variable values of the kinetic rate const. K1. Except for 3 cases, some degree of hypoxia was apparent in all lesions based on their nonzero k3 values.255Beck, R.; Röper, B.; Carlsen, J. M.; Huisman, M. C.; Lebschi, J. A.; Andratschke, N.; Picchio, M.; Souvatzoglou, M.; Machulla, M. J.; Piert, M. Pretreatment 18F-Faza Pet Predicts Success of Hypoxia-Directed Radiochemotherapy Using Tirapazamine. J. Nucl. Med. 2007, 48, 973– 980, DOI: 10.2967/jnumed.106.038570[Crossref], [PubMed], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVert7fJ&md5=6eb44d8a35836963557ad40768d4f7bfPretreatment 18F-FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamineBeck, Roswitha; Roeper, Barbara; Carlsen, Janette Maria; Huisman, Marc Cornelis; Lebschi, Julia Aloisia; Andratschke, Nicolaus; Picchio, Maria; Souvatzoglou, Michael; Machulla, Hans-Juergen; Piert, MorandJournal of Nuclear Medicine (2007), 48 (6), 973-980CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)We evaluated the predictive value of PET using the hypoxia tracer 18F-fluoroazomycin arabinoside (18F-FAZA) for success of radiotherapy in combination with tirapazamine, a specific cytotoxin for hypoxic cells. Methods: Imaging was performed on EMT6 tumor-bearing nude mice before allocating mice into 4 groups: radiochemotherapy (RCT: 8 fractions of 4.5 Gy within 4 d combined with tirapazamine, 14 mg/kg), radiotherapy alone (RT), chemotherapy alone (tirapazamine) (CHT), or control. Treatment success was assessed by several tumor growth assays, including tumor growth time from 70 to 500 μL and abs. growth delay (aGD). The median pretreatment 18F-FAZA tumor-to-background ratio served as a discriminator between "hypoxic" and "normoxic" tumors. Results: The mean tumor growth was significantly accelerated in hypoxic control tumors (growth time from 70 to 500 μL, 11.0 d) compared with normoxic control tumors (growth time from 70 to 500 μL, 15.6 d). Whereas RT delayed tumor growth regardless of the level of hypoxia, an additive beneficial therapeutic effect of tirapazamine to RT was obsd. only in hypoxic tumors (aGD, 12.9 d) but not in normoxic tumors (aGD, 6.0 d). Conclusion: This study provides compelling evidence that hypoxia imaging using 18F-FAZA PET is able to predict the success of RCT of tumor-bearing mice using the hypoxia-activated chemotherapeutic agent tirapazamine. Pretreatment 18F-FAZA PET, therefore, offers a way for the individualization of tumor treatment involving radiation. The data suggest that by reserving hypoxia-directed therapy to tumors with high 18F-FAZA uptake, improvement of the therapeutic ratio is possible, as the therapeutic effect of tirapazamine seems to be restricted to hypoxic tumors.256Michalski, M. H.; Chen, X. Molecular Imaging in Cancer Treatment. Eur. J. Nucl. Med. Mol. Imaging 2011, 38, 358– 377, DOI: 10.1007/s00259-010-1569-z[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsFKjsw%253D%253D&md5=a332e28c9ca0610d3c3ea0cb2131ae2bMolecular imaging in cancer treatmentMichalski, Mark H.; Chen, XiaoyuanEuropean Journal of Nuclear Medicine and Molecular Imaging (2011), 38 (2), 358-377CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. The success of cancer therapy can be difficult to predict, as its efficacy is often predicated upon characteristics of the cancer, treatment, and individual that are not fully understood or are difficult to ascertain. Monitoring the response of disease to treatment is therefore essential and has traditionally been characterized by changes in tumor vol. However, in many instances, this singular measure is insufficient for predicting treatment effects on patient survival. Mol. imaging allows repeated in vivo measurement of many crit. mol. features of neoplasm, such as metab., proliferation, angiogenesis, hypoxia, and apoptosis, which can be employed for monitoring therapeutic response. In this review, we examine the current methods for evaluating response to treatment and provide an overview of emerging PET mol. imaging methods that will help guide future cancer therapies.257Bonnitcha, P.; Grieve, S.; Figtree, G. Clinical Imaging of Hypoxia: Current Status and Future Directions. Free Radical Biol. Med. 2018, 126, 296– 312, DOI: 10.1016/j.freeradbiomed.2018.08.019[Crossref], [PubMed], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1Cgs7fM&md5=07c5e00e49b343085f8531ba873f050eClinical imaging of hypoxia: Current status and future directionsBonnitcha, Paul; Grieve, Stuart; Figtree, GemmaFree Radical Biology & Medicine (2018), 126 (), 296-312CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)Tissue hypoxia is a key feature of many important causes of morbidity and mortality. In pathologies such as stroke, peripheral vascular disease and ischemic heart disease, hypoxia is largely a consequence of low blood flow induced ischemia, hence perfusion imaging is often used as a surrogate for hypoxia to guide clin. diagnosis and treatment. Importantly, ischemia and hypoxia are not synonymous conditions as it is not universally true that well perfused tissues are normoxic or that poorly perfused tissues are hypoxic. In pathologies such as cancer, for instance, perfusion imaging and oxygen concn. are less well correlated, and oxygen concn. is independently correlated to radiotherapy response and overall treatment outcomes. In addn., the progression of many diseases is intricately related to maladaptive responses to the hypoxia itself. Thus there is potentially great clin. and scientific utility in direct measurements of tissue oxygenation. Despite this, imaging assessment of hypoxia in patients is rarely performed in clin. settings. This review summarises some of the current methods used to clin. evaluate hypoxia, the barriers to the routine use of these methods and the newer agents and techniques being explored for the assessment of hypoxia in pathol. processes.258Carlin, S.; Zhang, H.; Reese, M.; Ramos, N. N.; Chen, Q.; Ricketts, S. A. A Comparison of the Imaging Characteristics and Microregional Distribution of 4 Hypoxia PET Tracers. J. Nucl. Med. 2014, 55, 515– 521, DOI: 10.2967/jnumed.113.126615[Crossref], [PubMed], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXntleltrc%253D&md5=07f331b8b9fc09f5aaf5cfe3095836c4A comparison of the imaging characteristics and microregional distribution of 4 hypoxia PET tracersCarlin, Sean; Zhang, Hanwen; Reese, Megan; Ramos, Nicholas N.; Chen, Qing; Ricketts, Sally-AnnJournal of Nuclear Medicine (2014), 55 (3), 515-521CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)We compared the imaging characteristics and hypoxia selectivity of 4 hypoxia PET radiotracers (18F-fluoromisonidazole [18F-FMISO], 18F-flortanidazole [18F-HX4], 18F-fluoroazomycin arabinoside [18F-FAZA], and 64Cu-diacetyl-bis(N4-methylsemicarbazone) [64Cu-ATSM]) in a single murine xenograft tumor model condition using small-animal PET imaging and combined ex vivo autoradiog. and fluorescence immunohistochem. Methods: Nude mice bearing SQ20b xenograft tumors were administered 1 of 4 hypoxia PET tracers and images acquired 80-90 min after injection. Frozen sections from excised tumors were then evaluated for tracer distribution using digital autoradiog. and compared with histol. markers of tumor hypoxia (pimonidazole, carbonic anydrase 9 [CA9]) and vascular perfusion (Hoechst 33342). Results: The highest tumor uptake was obsd. with 64Cu-ATSM (max. standardized uptake values [SUVmax], 1.26 ± 0.13) and the lowest with 18F-FAZA (SUVmax, 0.41 ± 0.24). 18F-FMISO and 18F-HX4 had similar intermediate tumor uptake (SUVmax, 0.76 ± 0.38 and 0.65 ± 0.19, resp.). Digital autoradiographs of hypoxia tracer distribution were compared pixel by pixel with images of immunohistochem. strains. The fluorinated nitroimidazoles all showed radiotracer uptake increasing with pimonidazole and CA9 staining. 64Cu-ATSM showed the opposite pattern, with highest radiotracer uptake obsd. in regions with the lowest pimonidazole and CA9 staining. Conclusions: The fluorinated nitroimidazoles showed similar tumor distributions when compared with immunohistochem. markers of hypoxia. Variations in tumor standardized uptake value and normal tissue distribution may det. the most appropriate clin. setting for each tracer. 64Cu-ATSM showed the highest tumor accumulation and little renal clearance. However, the lack of correlation between 64Cu-ATSM distribution and immunohistochem. hypoxia markers casts some doubt on the hypoxia selectivity of 64Cu-ATSM.259Lewis, J.; McCarthy, D.; McCarthy, T.; Fujibayashi, Y.; Welch, M. Evaluation of 64Cu-ATSM In Vitro and In Vivo in a Hypoxic Tumor Model. J. Nucl. Med. 1999, 40, 177– 183[PubMed], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXos1aisA%253D%253D&md5=fa5e3bfe3cc7760173821501ec49e0adEvaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor modelLewis, Jason S.; McCarthy, Deborah W.; McCarthy, Timothy J.; Fujibayashi, Yasuhisa; Welch, Michael J.Journal of Nuclear Medicine (1999), 40 (1), 177-183CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine, Inc.)We have evaluated Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM), an effective marker for the delineation of hypoxic but viable tissue, in vitro in the EMT6 carcinoma cell line under varying degrees of hypoxia and compared it with the flow tracer 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) and the hypoxic tracer 18F-fluoromisonidazole (MISO). We have also compared the uptake of Cu-ATSM and Cu-PTSM in vivo and ex vivo in a murine animal model bearing the EMT6 tumor. Uptake of 64Cu-ATSM, 64Cu-PTSM and 18F-MISO in vitro into EMT6 cells was investigated at the dissolved oxygen concns. of 0, 1 × 103, 5 × 103, 5 × 104 and 2 × 105 ppm. Biodistribution performed at 1, 5, 10, 20 and 40 min compared 64Cu-ATSM with 64Cu-PTSM in BALB/c mice bearing EMT6 tumors. To det. long-term retention of 64Cu-ATSM, biodistribution was also performed at 1, 2 and 4 h. Ex vivo autoradiog. of tumor slices after co-injection of 60Cu-PTSM (60Cu, T1/2 = 23.7 min) and 64Cu-ATSM (64Cu, t1/2 = 12.7 h) into the same animal was performed. After 1 h, 64Cu-ATSM was taken up by EMT6 cells: 90% at 0 ppm, 77% at 1 × 103 ppm, 38% at 5 × 103 ppm, 35% at 5 × 104 ppm and 31% at 2 × 105 ppm. 18F-MISO also showed oxygen concn. dependent uptake, but with lower percentages than 64Cu-ATSM. 64Cu-PTSM showed 83%-85% uptake into the cells after 1 h, independent of oxygen concn. Biodistribution data of 64Cu-ATSM and 64Cu-PTSM showed optimal tumor uptake after 5 and 10 min, resp. (0.76% injected dose (ID)/organ for 64Cu-ATSM and 1.11%ID/organ for 64Cu-PTSM). Ex vivo imaging expts. showed 60Cu-PTSM uniform throughout the EMT6 tumor, but heterogeneous uptake of 64Cu-ATSM, indicative of selective trapping of 64Cu-ATSM into the hypoxic tumor cells. Cu-ATSM exhibits selectivity for hypoxic tumor tissue both in vivo and in vitro and may provide a successful diagnostic modality for the detection of tumor ischemia.260Pérès, E. A.; Toutain, J.; Paty, L. P.; Divoux, D.; Ibazizène, M.; Guillouet, S.; Barré, L.; Vidal, A.; Cherel, M.; Bourgeois, M.; Bernaudin, M.; Valable, S. 64Cu-Atsm/64Cu-Cl2 and Their Relationship to Hypoxia in Glioblastoma: A Preclinical Study. EJNMMI Res. 2019, 9, 114, DOI: 10.1186/s13550-019-0586-6[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisV2ksLbO&md5=cd672e128cf889f2c3a02483df10ddbf64Cu-ATSM/64Cu-Cl2 and their relationship to hypoxia in glioblastoma: a preclinical studyPeres, Elodie A.; Toutain, Jerome; Paty, Louis-Paul; Divoux, Didier; Ibazizene, Meziane; Guillouet, Stephane; Barre, Louisa; Vidal, Aurelien; Cherel, Michel; Bourgeois, Mickael; Bernaudin, Myriam; Valable, SamuelEJNMMI Research (2019), 9 (1), 114CODEN: ERJEAI; ISSN:2191-219X. (Springer GmbH)Here, we first analyzed uptake of Cu-ATSM and its less lipophilic counterpart Cu-Cl2 in the tumor over time in an orthotopic glioblastoma model. An in vitro study was also conducted to investigate the hypoxia-dependent copper uptake in tumor cells. We then further performed a comprehensive ex vivo study to compare 64Cu uptake to hypoxic markers, specific cellular reactions, and also transporter expression. Methods: μPET was performed 14 days (18F-FMISO), 15 days (64Cu-ATSM and 64Cu-Cl2), and 16 days (64Cu-ATSM and 64Cu-Cl2) after C6 cell inoculation. C6 cells were also grown in hypoxic workstation to analyze cellular uptake of Cu complexes in different oxygen levels. Results: In vivo results showed that Cu-ASTM and Cu-Cl2 accumulated in hypoxic areas of the tumors. Cu-ATSM also stained, to a lesser extent, non-hypoxic regions, such as regions of astrogliosis, with high expression of copper transporters and in particular DMT-1 and CTR1, and also characterized by the expression of elevated astrogliosis. Conclusion: In the present study, we show that Cu-complexes undoubtedly accumulate in hypoxic areas of the tumors. This uptake may be the reflection of a direct dependency to a redox metab. and also a reflection of hypoxic-induced overexpression of transporters. We also show that Cu-ATSM also stained non-hypoxic regions such as astrogliosis.261Lewis, J. S.; Sharp, T. L.; Laforest, R.; Fujibayashi, Y.; Welch, M. J. Tumor Uptake of Copper-Diacetyl-Bis(N4-Methylthiosemicarbazone): Effect of Changes in Tissue Oxygenation. J. Nucl. Med. 2001, 42, 655– 661[PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XksFSqt74%253D&md5=621f6dd32bfd748ba86389d0d2ea5535Tumor uptake of copper-diacetyl-bis(n4-methylthiosemicarbazone): Effect of changes in tissue oxygenationLewis, Jason S.; Sharp, Terry L.; Laforest, Richard; Fujibayashi, Yasuhisa; Welch, Michael J.Journal of Nuclear Medicine (2001), 42 (4), 655-661CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)We showed previously that, in vitro, copper-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) uptake is dependent on the oxygen concn. (pO2). We also showed that, in vivo, Cu-ATSM uptake is heterogeneous in animal tumors known to contain hypoxic fractions. This study was undertaken to confirm the pO2 dependence of this selective uptake in vivo by correlating Cu-ATSM uptake with measured tumor pO2. Expts. were performed with the 9L gliosarcoma rat model using a needle oxygen electrode to measure tissue pO2. Using PET and electronic autoradiog., Cu-ATSM uptake was measured in tumor tissue under various pO2 levels. The oxygen concn. within implanted tumors was manipulated by chem. means or by altering the inhaled oxygen content. A good correlation between low pO2 and high Cu-ATSM accumulation was obsd. Hydralazine administration in animals caused a decrease in the av. tumor pO2 from 28.61 ± 8.74 mm Hg to 20.81 ± 7.54 mm Hg in untreated control animals breathing atm. oxygen. It also caused the tumor uptake of Cu-ATSM to increase by 35%. Conversely, in animals breathing 100% oxygen, the av. tumor pO2 increased to 45.88 ± 15.9 mm Hg, and the tumor uptake of Cu-ATSM decreased to 48% of that of the control animals. PET of animals treated in a similar fashion yielded time-activity curves showing significantly higher retention of the tracer in hypoxic tissues than in oxygenated tissues. These data confirm that Cu-ATSM uptake in tissues in vivo is dependent on the tissue pO2, and that significantly greater uptake and retention occur in hypoxic tumor tissue. Therefore, the possible use of Cu-ATSM PET as a prognostic indicator in the management of cancer is further validated.262Colombié, M.; Gouard, S.; Frindel, M.; Vidal, A.; Chérel, M.; Kraeber-Bodéré, F.; Rousseau, C.; Bourgeois, M. Focus on the Controversial Aspects of 64Cu-ATSM in Tumoral Hypoxia Mapping by Pet Imaging. Front. Med. 2015, 2, 58, DOI: 10.3389/fmed.2015.00058[Crossref], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC283js1SntA%253D%253D&md5=5b5c86bc4b45450230b6d3f8df4d3b16Focus on the Controversial Aspects of (64)Cu-ATSM in Tumoral Hypoxia Mapping by PET ImagingColombie Mathilde; Gouard Sebastien; Frindel Mathieu; Vidal Aurelien; Cherel Michel; Rousseau Caroline; Kraeber-Bodere Francoise; Bourgeois MickaelFrontiers in medicine (2015), 2 (), 58 ISSN:2296-858X.Mapping tumor hypoxia is a great challenge in positron emission tomography (PET) imaging as the precise functional information of the biological processes is needed for many effective therapeutic strategies. Tumor hypoxia has been widely reported as a poor prognostic indicator and is often associated with tumor aggressiveness, chemo- and radio-resistance. An accurate diagnosis of hypoxia is a challenge and is crucial for providing accurate treatment for patients' survival benefits. This challenge has led to the emergence of new and novel PET tracers for the functional and metabolic characterization of tumor hypoxia non-invasively. Among these tracers, copper semicarbazone compound [64Cu]-diacetyl-bis(N (4)-methylthiosemicarbazone) (=64Cu-ATSM) has been developed as a tracer for hypoxia imaging. This review focuses on 64Cu-ATSM PET imaging and the concept is presented in two sections. The first section describes its in vitro development and pre-clinical testing and particularly its affinity in different cell lines. The second section describes the controversial reports on its specificity for hypoxia imaging. The review concludes that 64Cu-ATSM - more than a hypoxic tracer, exhibits tracer accumulation in tumor, which is linked to the redox potential and reactive oxygen species. The authors concluded that 64Cu-ATSNM is a marker of over-reduced cell state and thus an indirect marker for hypoxia imaging. The affinity of 64Cu-ATSM for over-reduced cells was observed to be a complex phenomenon. And to provide a definitive and convincing mechanism, more in vivo studies are needed to prove the diagnostic utility of 64Cu-ATSM.263Yuan, H.; Schroeder, T.; Bowsher, J. E.; Hedlund, L. W.; Wong, T.; Dewhirst, M. W. Intertumoral Differences in Hypoxia Selectivity of the PET Imaging Agent 64Cu(II)-Diacetyl-Bis(N4-Methylthiosemicarbazone). J. Nucl. Med. 2006, 47, 989– 998[PubMed], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XmtlWmtrg%253D&md5=805152c3ada8861fa94ae0e0a28c16daIntertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-Bis(N4-methylthiosemicarbazone)Yuan, Hong; Schroeder, Thies; Bowsher, James E.; Hedlund, Laurence W.; Wong, Terence; Dewhirst, Mark W.Journal of Nuclear Medicine (2006), 47 (6), 989-998CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)Cu-Diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) is a recently developed PET imaging agent for tumor hypoxia. However, its accuracy and reliability for measuring hypoxia have not been fully characterized in vivo. The aim of this study was to evaluate 64Cu-ATSM as a hypoxia PET marker by comparing autoradiog. distributions of 64Cu-ATSM with a well-established hypoxia marker drug, EF5. Methods: R3230 mammary adenocarcinomas (R3230Ac), fibrosarcomas (FSA), and 9L gliomas (9L) were used in the study. EF5 and Hoechst 33342, a vascular perfusion marker, were administered to the animal for immunohistochem. anal. 64Cu-ATSM microPET and autoradiog. were performed on the same animal. The tumor-to-muscle ratio (T/M ratio) and standardized uptake values (SUVs) were characterized for these 3 different types of tumors. Five types of images-microPET, autoradiog., EF5 immunostaining, Hoechst fluorescence vascular imaging, and hematoxylin-andeosin histol.-were superimposed, evaluated, and compared. Results: A significantly higher T/M ratio and SUV were seen for FSA compared with R3230Ac and 9L. Spatial correlation anal. between 64Cu-ATSM autoradiog. and EF5 immunostained images varied between the 3 tumor types. There was close correlation of 64Cu-ATSM uptake and hypoxia in R3230Ac and 9L tumors but not in FSA tumors. Interestingly, elevated 64Cu-ATSM uptake was obsd. in well-perfused areas in FSA, indicating a correlation between 64Cu-ATSM uptake and vascular perfusion as opposed to hypoxia. The same relationship was obsd. with 2 other hypoxia markers, pimonidazole and carbonic anhydrase IX, in FSA tumors. Breathing carbogen gas significantly decreased the hypoxia level measured by EF5 staining in FSA-bearing rats but not the uptake of 64Cu-ATSM. These results indicate that some other 64Cu-ATSM retention mechanisms, as opposed to hypoxia, are involved in this type of tumor. Conclusion: To our knowledge, this study is the first comparison between 64Cu-ATSM uptake and immunohistochem. in these 3 tumors. Although we have shown that 64Cu-ATSM is a valid PET hypoxia marker in some tumor types, but not for all, this tumor type-dependent hypoxia selectivity of 64Cu-ATSM challenges the use of 64Cu-ATSM as a universal PET hypoxia marker. Further studies are needed to define retention mechanisms for this PET marker.264Supuran, C. T. Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors. Metabolites 2017, 7, 48, DOI: 10.3390/metabo7030048[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1Sms70%253D&md5=a5c67e04f04323edb4f0b6701b8f665fCarbonic anhydrase inhibition and the management of hypoxic tumorsSupuran, Claudiu T.Metabolites (2017), 7 (3), 48/1-48/13CODEN: METALU; ISSN:2218-1989. (MDPI AG)Hypoxia and acidosis are salient features of many tumors, leading to a completely different metab. compared to normal cells. Two of the simplest metabolic products, protons and bicarbonate, are generated by the catalytic activity of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), with at least two of its isoforms, CA IX and XII, mainly present in hypoxic tumors. Inhibition of tumor-assocd. CAs leads to an impaired growth of the primary tumors, metastases and reduces the population of cancer stem cells, leading thus to a complex and beneficial anticancer action for this class of enzyme inhibitors. In this review, I will present the state of the art on the development of CA inhibitors (CAIs) targeting the tumor-assocd. CA isoforms, which may have applications for the treatment and imaging of cancers expressing them. Small mol. inhibitors, one of which (SLC-0111) completed Phase I clin. trials, and antibodies (girentuximab, discontinued in Phase III clin. trials) will be discussed, together with the various approaches used to design anticancer agents with a new mechanism of action based on interference with these crucial metabolites, protons and bicarbonate.265Park, W.; Bae, B. Chan; Na, K. A Highly Tumor-Specific Light-Triggerable Drug Carrier Responds to Hypoxic Tumor Conditions for Effective Tumor Treatment. Biomaterials 2016, 77, 227– 234, DOI: 10.1016/j.biomaterials.2015.11.014[Crossref], [PubMed], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVejs77M&md5=25d184cbd0383a45b1483aa4c8af5d0eA highly tumor-specific light-triggerable drug carrier responds to hypoxic tumor conditions for effective tumor treatmentPark, Wooram; Bae, Byoung-chan; Na, KunBiomaterials (2016), 77 (), 227-234CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Light-triggered drug delivery is among the most investigated stimulus-response strategies and has been widely explored in cancer treatment. However, the limited specificity of light-triggered drug delivery reduces the therapeutic efficacy and causes considerable undesirable side effects. In this work, we demonstrate a highly tumor-specific light-triggerable drug carrier (H-LTDC) induced by a combination of internal (i.e., tumor hypoxia) and external stimuli (i.e., light). The doxorubicin (DOX)-loaded H-LTDC was self-assembled from type-1-reactive oxygen species (ROStype1)-mediated degradable chondroitin sulfate (CS) conjugated with a photosensitizer (PS), Pheophorbide-a, which has a spherical shape and a uniform size distribution. Under hypoxic conditions, ROSType1 was mainly generated due to the electron-rich sulfate groups in the polysaccharide backbone. The ROStype1 generated by H-LTDC allowed laser-triggered drug release at low oxygen concns. From the in vitro cytotoxicity tests with colon cancer cells (HCT-116), under laser irradn., DOX-loaded H-LTDCs showed higher toxicity under hypoxic conditions than that under normoxic conditions. In vivo and ex vivo biodistribution studies demonstrated that H-LTDCs selectively accumulated in the tumor tissues. As a result, drug-loaded H-LTDCs exhibited high anti-tumor activity in vivo. Overall, we believe that this approach could represent a promising platform for the treatment of tumor and hypoxia-assocd. diseases without undesirable side effects.266Wilson, W. R.; Hay, M. P. Targeting Hypoxia in Cancer Therapy. Nat. Rev. Cancer 2011, 11, 393– 410, DOI: 10.1038/nrc3064[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmsVGmtbk%253D&md5=60b1b30b6d52120a0a76fba28a8e3429Targeting hypoxia in cancer therapyWilson, William R.; Hay, Michael P.Nature Reviews Cancer (2011), 11 (6), 393-410CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)A review. Hypoxia is a feature of most tumors, albeit with variable incidence and severity within a given patient population. It is a neg. prognostic and predictive factor owing to its multiple contributions to chemoresistance, radioresistance, angiogenesis, vasculogenesis, invasiveness, metastasis, resistance to cell death, altered metab., and genomic instability. Given its central role in tumor progression and resistance to therapy, tumor hypoxia might well be considered the best validated target that has yet to be exploited in oncol. However, despite an explosion of information on hypoxia, there are still major questions to be addressed if the long-standing goal of exploiting tumor hypoxia is to be realized. Here, we review the 2 main approaches, namely bioreductive prodrugs and inhibitors of mol. targets upon which hypoxic cell survival depends. We address the particular challenges and opportunities these overlapping strategies present, and discuss the central importance of emerging diagnostic tools for patient stratification in targeting hypoxia.267Lin, Q.; Bao, C.; Yang, Y.; Liang, Q.; Zhang, D.; Cheng, S.; Zhu, L. Highly Discriminating Photorelease of Anticancer Drugs Based on Hypoxia Activatable Phototrigger Conjugated Chitosan Nanoparticles. Adv. Mater. 2013, 25, 1981– 1986, DOI: 10.1002/adma.201204455[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXit1aht7k%253D&md5=3a5f58376b76109135636d48193e9fcbHighly Discriminating Photorelease of Anticancer Drugs Based on Hypoxia Activatable Phototrigger Conjugated Chitosan NanoparticlesLin, Qiuning; Bao, Chunyan; Yang, Yunlong; Liang, Qiannan; Zhang, Dasheng; Cheng, Shuiyu; Zhu, LinyongAdvanced Materials (Weinheim, Germany) (2013), 25 (14), 1981-1986CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)We have successfully constructed a novel hypoxia-activated one- or two-photon photoresponsive drug-release system based on a nitroimidazole-locked coumarin phototrigger. Compared with common photocontrolled release systems, the TAP (tumor hypoxia-activated phototrigger) exhibits highly discriminating photorelease of anticancer drug to hypoxic tumor cells, but not to aerobic healthy cells. Such a dramatic selectivity for tumor-killing potential is anticipated to achieve unprecedented strides in the development of photocontrolled drug-delivery systems, which will impact future chemotherapy for the treatment of solid tumors in vivo.268Qian, C.; Yu, J.; Chen, Y.; Hu, Q.; Xiao, X.; Sun, W.; Wang, C.; Feng, P.; Shen, Q. D.; Gu, Z. Light-Activated Hypoxia-Responsive Nanocarriers for Enhanced Anticancer Therapy. Adv. Mater. 2016, 28, 3313– 3320, DOI: 10.1002/adma.201505869[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjslGhsLk%253D&md5=9f47b4c6770c1cbe2bebccdc6dfe8cb9Light-Activated Hypoxia-Responsive Nanocarriers for Enhanced Anticancer TherapyQian, Chenggen; Yu, Jicheng; Chen, Yulei; Hu, Quanyin; Xiao, Xuanzhong; Sun, Wujin; Wang, Chao; Feng, Peijian; Shen, Qun-Dong; Gu, ZhenAdvanced Materials (Weinheim, Germany) (2016), 28 (17), 3313-3320CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)A light-activated hypoxia-responsive conjugated polymer-based nanocarrier is developed for efficiently producing singlet oxygen (1O2) and inducing hypoxia to promote release of its cargoes in tumor cells, leading to enhanced antitumor efficacy. This dual-responsive nanocarrier provides an innovative design guideline for enhancing traditional photodynamic therapeutic efficacy integrated with a controlled drug-release modality.269Mitton, D.; Ackroyd, R. A Brief Overview of Photodynamic Therapy in Europe. Photodiagn. Photodyn. Ther. 2008, 5, 103– 111, DOI: 10.1016/j.pdpdt.2008.04.004[Crossref], [PubMed], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVCks7%252FO&md5=42a2c32a628a8c3750307b77bac7d4e2A brief overview of photodynamic therapy in EuropeMitton, D.; Ackroyd, R.Photodiagnosis and Photodynamic Therapy (2008), 5 (2), 103-111CODEN: PPTHBF; ISSN:1572-1000. (Elsevier B.V.)A review. Photodynamic effect was a chance discovery early in the 1900s, demonstrating the lethal effects of light activated chems. on living cells. Although the application of the principles of photodynamic effect to patients' treatment and what became photodynamic therapy (PDT) was practiced in 1960s and 1970s, clin. trials were only started in the 1980s, following successful synthesis of clin. usable photosensitizers (drugs) and the manufg. of light sources. We briefly review and highlight some of the landmarks of the development of clin. PDT in Europe.270Floeth, F. W.; Sabel, M.; Ewelt, C.; Stummer, W.; Felsberg, J.; Reifenberger, G.; Steiger, H. J.; Stoffels, G.; Coenen, H. H.; Langen, K. J. Comparison of 18F-FET PET and 5-ALA Fluorescence in Cerebral Gliomas. Eur. J. Nucl. Med. Mol. Imaging 2011, 38, 731– 741, DOI: 10.1007/s00259-010-1690-z[Crossref], [PubMed], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXivFyksL8%253D&md5=231fd8a7e67e4e6cc7292d9360091c15Comparison of 18F-FET PET and 5-ALA fluorescence in cerebral gliomasFloeth, Frank Willi; Sabel, Michael; Ewelt, Christian; Stummer, Walter; Felsberg, Joerg; Reifenberger, Guido; Steiger, Hans Jakob; Stoffels, Gabriele; Coenen, Heinz Hubert; Langen, Karl-JosefEuropean Journal of Nuclear Medicine and Molecular Imaging (2011), 38 (4), 731-741CODEN: EJNMA6; ISSN:1619-7070. (Springer)Purpose: The aim of the study was to compare presurgical 18F-fluoroethyl-L-tyrosine (18F-FET) uptake and Gd-diethylenetriaminepentaacetic acid (DTPA) enhancement on MRI (Gd) with intraoperative 5-aminolevulinic acid (5-ALA) fluorescence in cerebral gliomas. Methods: 18F-FET positron emission tomog. (PET) was performed in 30 patients with brain lesions suggestive of diffuse WHO grade II or III gliomas on MRI. PET and MRI data were coregistered to guide neuronavigated biopsies before resection. After oral application of 5-ALA, 38 neuronavigated biopsies were taken from predefined tumor areas that were pos. or neg. for 18F-FET or Gd and checked for 5-ALA fluorescence. 18F-FET uptake with a mean tumor to brain ratio ≥1.6 was rated as pos. Results: Of 38 biopsies, 21 corresponded to high-grade glioma tissue (HGG) of WHO grade III (n = 19) or IV (n = 2) and 17 biopsies to low-grade glioma tissue (LGG) of WHO grade II. In biopsies corresponding to HGG, 18F-FET PET was pos. in 86% (18/21), but 5-ALA and Gd in only 57% (12/21). A mismatch between Gd and 5-ALA was obsd. in 6 of 21 cases of HGG biopsy samples (3 Gd-pos./5-ALA-neg. and 3 Gd-neg./5-ALA-pos.). In biopsies corresponding to LGG, 18F-FET was pos. in 41% (7/17), while 5-ALA and Gd were neg. in all but one instance. All tumor areas with 5-ALA fluorescence were pos. on 18F-FET PET. Conclusion: There are differences between 18F-FET and 5-ALA uptake in cerebral gliomas owing to a limited sensitivity of 5-ALA to detect tumor tissue esp. in LGG. 18F-FET PET is more sensitive to detect glioma tissue than 5-ALA fluorescence and should be considered as an addnl. tool in resection planning.271Quirk, B. J.; Brandal, G.; Donlon, S.; Vera, J. C.; Mang, T. S.; Foy, A. B.; Lew, S. M.; Girotti, A. W.; Jogal, S.; LaViolette, P. S.; Connelly, J. M.; Whelan, H. T. Photodynamic Therapy (PDT) for Malignant Brain Tumors - Where Do We Stand?. Photodiagn. Photodyn. Ther. 2015, 12, 530– 544, DOI: 10.1016/j.pdpdt.2015.04.009[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfisV2hug%253D%253D&md5=51773677f7c1fd530c521e62255fa704Photodynamic therapy (PDT) for malignant brain tumors--where do we stand?Quirk Brendan J; Connelly Jennifer M; Brandal Garth; Donlon Steven; Vera Juan Carlos; Mang Thomas S; Foy Andrew B; Lew Sean M; Girotti Albert W; Jogal Sachin; LaViolette Peter S; Whelan Harry TPhotodiagnosis and photodynamic therapy (2015), 12 (3), 530-44 ISSN:.INTRODUCTION: What is the current status of photodynamic therapy (PDT) with regard to treating malignant brain tumors? Despite several decades of effort, PDT has yet to achieve standard of care. PURPOSE: The questions we wish to answer are: where are we clinically with PDT, why is it not standard of care, and what is being done in clinical trials to get us there. METHOD: Rather than a meta-analysis or comprehensive review, our review focuses on who the major research groups are, what their approaches to the problem are, and how their results compare to standard of care. Secondary questions include what the effective depth of light penetration is, and how deep can we expect to kill tumor cells. CURRENT RESULTS: A measurable degree of necrosis is seen to a depth of about 5mm. Cavitary PDT with hematoporphyrin derivative (HpD) results are encouraging, but need an adequate Phase III trial. Talaporfin with cavitary light application appears promising, although only a small case series has been reported. Foscan for fluorescence guided resection (FGR) plus intraoperative cavitary PDT results were improved over controls, but are poor compared to other groups. 5-Aminolevulinic acid-FGR plus postop cavitary HpD PDT show improvement over controls, but the comparison to standard of care is still poor. CONCLUSION: Continued research in PDT will determine whether the advances shown will mitigate morbidity and mortality, but certainly the potential for this modality to revolutionize the treatment of brain tumors remains. The various uses for PDT in clinical practice should be pursued.272Suzuki, H. I.; Katsura, A.; Matsuyama, H.; Miyazono, K. MicroRNA Regulons in Tumor Microenvironment. Oncogene 2015, 34, 3085– 3094, DOI: 10.1038/onc.2014.254[Crossref], [PubMed], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlKrtb7M&md5=2f88e10500d2ea7763a2a4492a82b24dMicroRNA regulons in tumor microenvironmentSuzuki, H. I.; Katsura, A.; Matsuyama, H.; Miyazono, K.Oncogene (2015), 34 (24), 3085-3094CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)A review. Cancer initiation and progression are defined by the behavior of cancer cells per se and the development of tumor tissues, both of which are modulated by crosstalk between cancer cells and the surrounding microenvironment. Advances in cancer research have highlighted the significance of const. evolution of the tumor microenvironment, leading to tumor formation, metastasis and refractoriness to therapy. MicroRNAs (miRNAs) are small non-coding RNAs that function as major players of posttranscriptional gene regulation in diverse biol. processes. They function as both tumor suppressors and promoters in many aspects of the autonomous behavior of cancer cells. Theor., dysfunction in the gene regulatory networks of cancer cells is one of the major driving forces for alterations of ostensibly normal surrounding cells. In this context, the core targets of miRNAs, termed miRNA regulons, are currently being expanded to include various modulators of the tumor microenvironment. Recent advances have highlighted two important roles played by miRNAs in the evolution of tumor microenvironments: miRNAs in tumor cells transform the microenvironment via non-cell-autonomous mechanisms, and miRNAs in neighboring cells stabilize cancer hallmark traits. These observations epitomize the distal and proximal functions of miRNAs in tumor microenvironments, resp. Such regulation by miRNAs affects tumor angiogenesis, immune invasion and tumor-stromal interactions. This review summarizes recent findings on the mechanisms of miRNA-mediated regulation of tumor microenvironments, with a perspective on the design of therapeutic interventions.273Waghorn, P. A.; Jones, M. W.; Theobald, M. B. M.; Arrowsmith, R. L.; Pascu, S. I.; Botchway, S. W.; Faulkner, S.; Dilworth, J. R. Shining Light on the Stability of Metal Thiosemicarbazonate Complexes in Living Cells by FLIM. Chem. Sci. 2013, 4, 1430– 1441, DOI: 10.1039/c2sc21489j[Crossref], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtlymtr4%253D&md5=0ed6032322f73ad8a00cb59979ce8248Shining light on the stability of metal thiosemicarbazonate complexes in living cells by FLIMWaghorn, Philip A.; Jones, Michael W.; Theobald, Mark B. M.; Arrowsmith, Rory L.; Pascu, Sofia I.; Botchway, Stanley W.; Faulkner, Stephen; Dilworth, Jonathan R.Chemical Science (2013), 4 (4), 1430-1441CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Complexes of Cu(II), Ni(II) and Zn(II) have been prepd. with bis(thiosemicarbazonate) ligands bearing a pendant Bodipy fluorophore both with (ATSMBodipy) and without (GTSBodipy) backbone Me groups. Biophys. anal. using steady state confocal laser scanning fluorescence images and excited state fluorescence lifetime imaging microscopy (FLIM) data obtained from live cells under aerobic uptake conditions has uniquely allowed both the spatial distribution and degree of dissocn. of the complexes to be assessed. The CuATSMBodipy complex is virtually intact after 20 min and 1 h whereas the corresponding CuGTSBodipy complex is totally dissocd. The complexes ZnATSMBodipy and NiATSMBodipy show little evidence for dissocn. The relevance of this data to the biomedical applications of bis(thiosemicarbazonate) complexes for imaging applications and implications for the treatment of disease such as Alzheimer's and the PET imaging of hypoxia are discussed.274Nie, S.; Xing, Y.; Kim, G. J.; Simons, J. W. Nanotechnology Applications in Cancer. Annu. Rev. Biomed. Eng. 2007, 9, 257– 288, DOI: 10.1146/annurev.bioeng.9.060906.152025[Crossref], [PubMed], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtVehtLbK&md5=c4904039a339482da4a73133587cff24Nanotechnology applications in cancerNie, Shuming; Xing, Yun; Kim, Gloria J.; Simons, Jonathan W.Annual Review of Biomedical Engineering (2007), 9 (), 257-288CODEN: ARBEF7; ISSN:1523-9829. (Annual Reviews Inc.)A review. Cancer nanotechnol. is an interdisciplinary area of research in science, engineering, and medicine with broad applications for mol. imaging, mol. diagnosis, and targeted therapy. The basic rationale is that nanometer-sized particles, such as semiconductor quantum dots and iron oxide nanocrystals, have optical, magnetic, or structural properties that are not available from mols. or bulk solids. When linked with tumor targeting ligands such as monoclonal antibodies, peptides, or small mols., these nanoparticles can be used to target tumor antigens (biomarkers) as well as tumor vasculatures with high affinity and specificity. In the mesoscopic size range of 5-100 nm diam., nanoparticles also have large surface areas and functional groups for conjugating to multiple diagnostic (e.g., optical, radioisotopic, or magnetic) and therapeutic (e.g., anticancer) agents. Recent advances have led to bioaffinity nanoparticle probes for mol. and cellular imaging, targeted nanoparticle drugs for cancer therapy, and integrated nanodevices for early cancer detection and screening. These developments raise exciting opportunities for personalized oncol. in which genetic and protein biomarkers are used to diagnose and treat cancer based on the mol. profiles of individual patients.275McCarthy, J. R. Multifunctional Agents for Concurrent Imaging and Therapy in Cardiovascular Disease. Adv. Drug Delivery Rev. 2010, 62, 1023– 1030, DOI: 10.1016/j.addr.2010.07.004[Crossref], [PubMed], [CAS], Google Scholar275https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVGitb7O&md5=20d0a7885d013bbb4d05b7b29facc768Multifunctional agents for concurrent imaging and therapy in cardiovascular diseaseMcCarthy, Jason R.Advanced Drug Delivery Reviews (2010), 62 (11), 1023-1030CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. The development of agents for the simultaneous detection and treatment of disease has recently gained significant attention. These multifunctional theranostic agents posses a no. of advantages over their monofunctional counterparts, as they potentially allow for the concomitant detn. of agent localization, release, and efficacy. Whereas the development of these agents for use in cancers has received the majority of the attention, their use in cardiovascular disease is steadily increasing. As such, this review summarized some of the most poignant recent advances in the development of theranostic agents for the treatment of this class of diseases.276Warenius, H. M. Technological Challenges of Theranostics in Oncology. Expert Opin. Med. Diagn. 2009, 3, 381– 393, DOI: 10.1517/17530050902893295[Crossref], [PubMed], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXps1Wms7s%253D&md5=2eed0d656c176186154150b461816223Technological challenges of theranostics in oncologyWarenius, Hilmar M.Expert Opinion on Medical Diagnostics (2009), 3 (4), 381-393CODEN: EOMDA9; ISSN:1753-0059. (Informa Healthcare)A review. Background: Although the term theranostics has been coined only fairly recently, attempts to relate the level of biomarkers to therapeutic response in the oncol. clinic go back several decades. After a long period in which a limited no. of individual theranostic mol. biomarkers gained general clin. acceptance, extremely powerful genomic and proteomic technologies have now emerged. Methods: These technologies, reviewed here, promise a potential revolution in our ability to predict therapeutic response in cancer, and by so doing, guide new anticancer drugs more successfully into clin. oncol. practice. A full understanding of the detailed mol. nature of clin. cancer is, however, still evolving. The need for appropriate models of the highly complex disease, against which we are attempting to direct effective therapy more accurately, is also addressed. These should include an understanding of genomic and proteomic heterogeneity, genetic instability and systems biol. models of cancer that take into account recent demonstrations of the vastly increased mutational state of the av. clin. cancer as compared with the normal cell(s) from which it arose. Conclusion: The way forward in theranostics is, arguably, less dependent on further improvements in the already powerful genomic and proteomic technologies themselves than on our improved understanding of how we should apply them to the complex reality of the av. clin. cancer.277Habermeyer, B.; Guilard, R. Some Activities of Porphychem Illustrated by the Applications of Porphyrinoids in PDT, PIT and PDI. Photochem. Photobiol. Sci. 2018, 17, 1675– 1690, DOI: 10.1039/C8PP00222C[Crossref], [PubMed], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFSqurnJ&md5=97483e3612cd1bfb26c77ca5c7443cd1Some activities of PorphyChem illustrated by the applications of porphyrinoids in PDT, PIT and PDIHabermeyer, B.; Guilard, R.Photochemical & Photobiological Sciences (2018), 17 (11), 1675-1690CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)Photodynamic therapy is an innovative approach to treat diverse cancers and diseases that involves the use of photosensitizing agents along with light of an appropriate wavelength to generate cytotoxic reactive oxygen species. Among the collection of potential dye candidates, porphyrinoids (i.e. porphyrins, chlorins, and phthalocyanines) are probably the most promising photosensitizers for PDT applications. This review shows the great potential of these derivs. for their industrial development in the field of health through different applications in photodynamic therapy (PDT), photoimmunotherapy (PIT), ophthalmol., dermatol. and photodynamic inactivation (PDI). The purpose of this survey is also to show the new trends and evolutions in these fields.278Singh, S.; Aggarwal, A.; Bhupathiraju, N. V. S. D. K.; Arianna, G.; Tiwari, K.; Drain, C. M. Glycosylated Porphyrins, Phthalocyanines, and Other Porphyrinoids for Diagnostics and Therapeutics. Chem. Rev. 2015, 115, 10261– 10306, DOI: 10.1021/acs.chemrev.5b00244[ACS Full Text], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVahs7rE&md5=64c404241a7ed4daf5e1c0eb5f4a93adGlycosylated Porphyrins, Phthalocyanines, and Other Porphyrinoids for Diagnostics and TherapeuticsSingh, Sunaina; Aggarwal, Amit; Bhupathiraju, N. V. S. Dinesh K.; Arianna, Gianluca; Tiwari, Kirran; Drain, Charles MichaelChemical Reviews (Washington, DC, United States) (2015), 115 (18), 10261-10306CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Agents involved in photodynamic therapy (PDT) are discussed.279Zhang, Y.; Lovell, J. F. Recent Applications of Phthalocyanines and Naphthalocyanines for Imaging and Therapy. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2017, 9, e1420, DOI: 10.1002/wnan.1420280Shao, S.; Rajendiran, V.; Lovell, J. F. Metalloporphyrin Nanoparticles: Coordinating Diverse Theranostic Functions. Coord. Chem. Rev. 2019, 379, 99– 120, DOI: 10.1016/j.ccr.2017.09.002[Crossref], [PubMed], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFCqs7zK&md5=c273f293d0fbe111c114b514237f966eMetalloporphyrin nanoparticles: Coordinating diverse theranostic functionsShao, Shuai; Rajendiran, Venugopal; Lovell, Jonathan F.Coordination Chemistry Reviews (2019), 379 (), 99-120CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)Metalloporphyrins serve key roles in natural biol. processes and also have demonstrated utility for biomedical applications. They can be encapsulated or grafted in conventional nanoparticles or can self-assemble themselves at the nanoscale. A wide range of metals can be stably chelated either before or after porphyrin nanoparticle formation, without the necessity of any addnl. chelator chem. The addn. of metals can substantially alter a range of behaviors such as modulating phototherapeutic efficacy; conferring responsiveness to biol. stimuli; or providing contrast for magnetic resonance, positron emission or surface enhanced Raman imaging. Chelated metals can also provide a convenient handle for bioconjugation with other mols. via axial coordination. This review provides an overview of some recent biomedical, nanoparticulate approaches involving gain-of-function metalloporphyrins and related mols.281Tsolekile, N.; Nelana, S.; Oluwafemi, O. S. Porphyrin as Diagnostic and Therapeutic Agent. Molecules 2019, 24, 2669, DOI: 10.3390/molecules24142669[Crossref], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVygs7fM&md5=a1705a5ae905ba0031d0f64a10d28b3fPorphyrin as diagnostic and therapeutic agentTsolekile, Ncediwe; Nelana, Simphiwe; Oluwafemi, Oluwatobi SamuelMolecules (2019), 24 (14), 2669CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)The synthesis and application of porphyrins has seen a huge shift towards research in porphyrin bio-mol. based systems in the past decade. The preferential localization of porphyrins in tumors, as well as their ability to generate reactive singlet oxygen and low dark toxicities has resulted in their use in therapeutic applications such as photodynamic therapy. However, their inherent lack of bio-distribution due to water insoly. has shifted research into porphyrin-nanomaterial conjugated systems to address this challenge. This has broadened their bio-applications, viz. bio-sensors, fluorescence tracking, in vivo magnetic resonance imaging (MRI), and positron emission tomog. (PET)/CT imaging to photo-immuno-therapy just to highlight a few. This paper reviews the unique theranostic role of porphyrins in disease diagnosis and therapy. The review highlights porphyrin conjugated systems and their applications. The review ends by bringing current challenges and future perspectives of porphyrin based conjugated systems and their resp. applications into light.282Pucelik, B.; Paczyński, R.; Dubin, G.; Pereira, M. M.; Arnaut, L. G.; Dąbrowski, J. M. Properties of Halogenated and Sulfonated Porphyrins Relevant for the Selection of Photosensitizers in Anticancer and Antimicrobial Therapies. PLoS One 2017, 12, e0185984, DOI: 10.1371/journal.pone.0185984[Crossref], [PubMed], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFegt7nO&md5=2b930b74017f765218702bcdee58bf23Properties of halogenated and sulfonated porphyrins relevant for the selection of photosensitizers in anticancer and antimicrobial therapiesPucelik, Barbara; Paczynski, Robert; Dubin, Grzegorz; Pereira, Mariette M.; Arnaut, Luis G.; Dabrowski, Janusz M.PLoS One (2017), 12 (10), e0185984/1-e0185984/22CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)The impact of substituents on the photochem. and biol. properties of tetraphenylporphyrin-based photosensitizers for photodynamic therapy of cancer (PDT) as well as photodynamic inactivation of microorganisms (PDI) was examd. Spectroscopic and physicochem. properties were related with therapeutic efficacy in PDT of cancer and PDI of microbial cells in vitro. Less polar halogenated, sulfonamide porphyrins were most readily taken up by cells compared to hydrophilic and anionic porphyrins. The uptake and PDT of a hydrophilic porphyrin was significantly enhanced with incorporation in polymeric micelles (Pluronic L121). Photodynamic inactivation studies were performed against Gram-pos. (S. aureus, E. faecalis), Gram-neg. bacteria (E. coli, P. aeruginosa, S. marcescens) and fungal yeast (C. albicans). We obsd. a 6 logs redn. of S. aureus after irradn. (10 J/cm2) in the presence of 20μM of hydrophilic porphyrin, but this was not improved with incorporation in Pluronic L121. A 2-3 logs redn. was obtained for E. coli using similar doses, and a decrease of 3-4 logs was achieved for C. albicans. Rational substitution of tetraphenylporphyrins improves their photodynamic properties and informs on strategies to obtain photosensitizers for efficient PDT and PDI. However, the design of the photosensitizers must be accompanied by the development of tailored drug formulations.283Xie, J.; Lee, S.; Chen, X. Nanoparticle-Based Theranostic Agents. Adv. Drug Delivery Rev. 2010, 62, 1064– 1079, DOI: 10.1016/j.addr.2010.07.009[Crossref], [PubMed], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVGitb7J&md5=87873807b175591d2fa5db581677acb2Nanoparticle-based theranostic agentsXie, Jin; Lee, Seulki; Chen, XiaoyuanAdvanced Drug Delivery Reviews (2010), 62 (11), 1064-1079CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. Theranostic nanomedicine is emerging as a promising therapeutic paradigm. It takes advantage of the high capacity of nanoplatforms to ferry cargo and loads onto them both imaging and therapeutic functions. The resulting nanosystems, capable of diagnosis, drug delivery and monitoring of therapeutic response, are expected to play a significant role in the dawning era of personalized medicine, and much research effort was devoted toward that goal. A convenience in constructing such function-integrated agents is that many nanoplatforms are already, themselves, imaging agents. Their well-developed surface chem. makes it easy to load them with pharmaceutics and promote them to be theranostic nanosystems. Iron oxide nanoparticles, quantum dots, carbon nanotubes, gold nanoparticles and silica nanoparticles, were previously well investigated in the imaging setting and are candidate nanoplatforms for building up nanoparticle-based theranostics. In the current article, the authors will outline the progress along this line, organized by the category of the core materials. The authors will focus on construction strategies and will discuss the challenges and opportunities assocd. with this emerging technol.284Lammers, T.; Kiessling, F.; Hennink, W. E.; Storm, G. Nanotheranostics and Image-Guided Drug Delivery: Current Concepts and Future Directions. Mol. Pharmaceutics 2010, 7, 1899– 1912, DOI: 10.1021/mp100228v[ACS Full Text], [CAS], Google Scholar284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1GgurzF&md5=c0f1a26ed421514a5422d162807f38caNanotheranostics and Image-Guided Drug Delivery: Current Concepts and Future DirectionsLammers, Twan; Kiessling, Fabian; Hennink, Wim E.; Storm, GertMolecular Pharmaceutics (2010), 7 (6), 1899-1912CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)A review. Nanomedicine formulations aim to improve the biodistribution and the target site accumulation of systemically applied (chemo-) therapeutics. Various different passively and actively targeted nanomedicines have been evaluated over the years, based e.g. on liposomes, polymers, micelles and antibodies, and a significant amt. of (pre-) clin. evidence has been obtained showing that these 5-200 nm sized carrier materials are able to improve the therapeutic index of low-mol.-wt. drugs. Besides for therapeutic purposes, however, nanomedicine formulations have also been more and more used for imaging applications, as well as, in recent years, for theranostic approaches, i.e. for systems and strategies in which disease diagnosis and therapy are combined. Potential applications of theranostic nanomedicine formulations range from the noninvasive assessment of the biodistribution and the target site accumulation of low-mol.-wt. drugs, and the visualization of drug distribution and drug release at the target site, to the optimization of strategies relying on triggered drug release, and the prediction and real-time monitoring of therapeutic responses. Nanotheranostic systems are consequently considered to be highly suitable systems for (pre-) clin. implementation, not only because they might assist in better understanding various important aspects of the drug delivery process, and in developing better drug delivery systems, but also because they might contribute to realizing the potential of "personalized medicine", and to developing more effective and less toxic treatment regimens for individual patients.285Darwent, J. R.; McCubbin, I.; Phillips, D. Excited Singlet and Triplet State Electron-Transfer Reactions of Aluminium(III) Sulphonated Phthalocyanine. J. Chem. Soc., Faraday Trans. 2 1982, 78, 347– 357, DOI: 10.1039/f29827800347[Crossref], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38Xkt1ejsLY%253D&md5=99b051b32a195d942d385811a2f7c89dExcited singlet and triplet state electron-transfer reactions of aluminum(III) sulfonated phthalocyanineDarwent, James R.; McCubbin, Ian; Phillips, D.Journal of the Chemical Society, Faraday Transactions 2: Molecular and Chemical Physics (1982), 78 (2), 347-57CODEN: JCFTBS; ISSN:0300-9238.Conventional and ns flash photolysis were used to study the excited-state reactions of Al(III) sulfonated phthalocyanine (I) with benzohydroquinone (II), methylologen (III), benzylviologen (IV) and di-Na anthraquinone-2,6-disulfonate (V). The fluorescent state of I was quenched by all of these reagents at rates close to the diffusion-controlled limit; however, no sep. electron-transfer products were detected from the reaction with IV, III, or V despite the electrostatic repulsion between the phthalocyanine and semiquinone radical anions. In contrast, quenching by II produced a transient (τ ≃100 ns), which is attributed to a long-lived geminate ion pair, from which sepd. ions escaped. The triplet state of I did not react with V, IV, or III, but was quenched by O2 and II. Sepd. ions were produced 3 times as efficiently from the triplet-state reaction of I with II than from the excited singlet-state reaction.286Couleaud, P.; Morosini, V.; Frochot, C.; Richeter, S.; Raehm, L.; Durand, J. O. Silica-Based Nanoparticles for Photodynamic Therapy Applications. Nanoscale 2010, 2, 1083– 1095, DOI: 10.1039/c0nr00096e[Crossref], [PubMed], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlOntbjO&md5=1c15cd616d19f245724a4f717685fbc4Silica-based nanoparticles for photodynamic therapy applicationsCouleaud, Pierre; Morosini, Vincent; Frochot, Celine; Richeter, Sebastien; Raehm, Laurence; Durand, Jean-OlivierNanoscale (2010), 2 (7), 1083-1095CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)A review. Silica-based nanoparticles for applications in photodynamic therapy (PDT) have emerged as a promising field for the treatment of cancer. In this review, based on the pathway the photosensitizer is entrapped inside the silica matrix, the different methods for the synthesis of silica-based nanoparticles are described from the pioneering works to the latest achievements which concern multifunctional nanoplatforms, up-converting nanoparticles, two-photon PDT, vectorization and in vivo applications.287Oluwole, D. O.; Nyokong, T. Photophysicochemical Behaviour of Metallophthalocyanines When Doped onto Silica Nanoparticles. Dyes Pigm. 2017, 136, 262– 272, DOI: 10.1016/j.dyepig.2016.08.053[Crossref], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVKqsLvE&md5=d2b9ad0f82a554821e032978a985323ePhotophysicochemical behavior of metallophthalocyanines when doped onto silica nanoparticlesOluwole, David O.; Nyokong, TebelloDyes and Pigments (2017), 136 (), 262-272CODEN: DYPIDX; ISSN:0143-7208. (Elsevier Ltd.)Aluminum(III) chloride 2,9(10),16(17),23(24)-tetra-(4-tert-butylphenoxy)phthalocyanine (1), zinc(II) 2,9(10),16(17),23(24)-tetra-(4-tert-butylphenoxy)phthalocyanine (2), zinc(II) 1,8(11),15(18),22(25)-tetra-(4-tert-butylphenoxy) phthalocyanine (3) and zinc(II) 2,9(10),16(17),23(24)-tetra-(4-carboxylphenoxy) phthalocyanine (4) were doped onto silica nanoparticles (SiNPs). There were no significant changes in fluorescence quantum yields and lifetimes of the metallophthalocyanines ( MPcs) when doped onto SiNPs. The triplet quantum yields of the MPcs alone range from 0.22 to 0.85 and in the presence of SiNPs the values range from 0.17 to 0.89. We obsd. a general decrease of triplet quantum yields of phthalocyanines in the conjugates except for 2 where there was an increase. The values were highly affected by aggregation. Complexes 1 and 3 were highly aggregated when doped onto SiNPs, while 2 and 4 did not show much aggregation.288Tang, L.; Cheng, J. Nonporous Silica Nanoparticles for Nanomedicine Application. Nano Today 2013, 8, 290– 312, DOI: 10.1016/j.nantod.2013.04.007[Crossref], [PubMed], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXptVaht70%253D&md5=1527aaf13e5d08d732e7d35d7426d1e5Nonporous silica nanoparticles for nanomedicine applicationTang, Li; Cheng, JianjunNano Today (2013), 8 (3), 290-312CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)A review. Nanomedicine, the use of nanotechnol. for biomedical applications, has potential to change the landscape of the diagnosis and therapy of many diseases. In the past several decades, the advancement in nanotechnol. and material science has resulted in a large no. of org. and inorg. nanomedicine platforms. Silica nanoparticles (NPs), which exhibit many unique properties, offer a promising drug delivery platform to realize the potential of nanomedicine. Mesoporous silica NPs have been extensively reviewed previously. Here we review the current state of the development and application of nonporous silica NPs for drug delivery and mol. imaging.289Huang, D.; Hung, Y.; Ko, B.; Hsu, S.; Chen, W.; Chien, C.; Tsai, C.; Kuo, C.; Kang, J.; Yang, C.; Mou, C.; Chen, Y. Highly Efficient Cellular Labeling of Mesoporous Nanoparticles in Human Mesenchymal Stem Cells: Implication for Stem Cell Tracking. FASEB J. 2005, 19, 2014– 2016, DOI: 10.1096/fj.05-4288fje[Crossref], [PubMed], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtlSmtb7I&md5=9a5f85d551a9fafedf719e3b9bacfd65Highly efficient cellular labeling of mesoporous nanoparticles in human mesenchymal stem cells: implication for stem cell trackingHuang, Dong-Ming; Hung, Yann; Ko, Bor-Sheng; Hsu, Szu-Chun; Chen, Wei-Hsuan; Chien, Chung-Liang; Tsai, Chih-Pin; Kuo, Chieh-Ti; Kang, Ju-Chiun; Yang, Chung-Shi; Mou, Chung-Yuan; Chen, Yao-ChangFASEB Journal (2005), 19 (14), 2014-2016CODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)Tracking the distribution of stem cells is crucial to their therapeutic use. However, the usage of current vectors in cellular labeling is restricted by their low internalizing efficiency. Here, we reported a cellular labeling approach with a novel vector composed of mesoporous silica nanoparticles (MSNs) conjugated with fluorescein isothiocyanate in human bone marrow mesenchymal stem cells and 3T3-L1 cells, and the mechanism about fluorescein isothiocyanate-conjugated MSNs (FITC-MSNs) internalization was studied. FITC-MSNs were efficiently internalized into mesenchymal stem cells and 3T3-L1 cells even in short-term. incubation. The process displayed a time- and concn.-dependent manner and was dependent on clathrin-mediated endocytosis. In addn., clathrin-dependent endocytosis seemed to play a decisive role on more internalization and longer stay of FITC-MSNs in mesenchymal stem cells than in 3T3-L1 cells. The internalization of FITC-MSNs did not affect the cell viability, proliferation, immunophenotype, and differentiation potential of mesenchymal stem cells, and 3T3-L1 cells. Finally, FITC-MSNs could escape from endolysosomal vesicles and were retained the architectonic integrity after internalization. We conclude that the advantages of biocompatibility, durability, and higher efficiency in internalization suit MSNs to be a better vector for stem cell tracking than others currently used.290Lin, Y. S.; Wu, S. H.; Hung, Y.; Chou, Y. H.; Chang, C.; Lin, M. L.; Tsai, C. P.; Mou, C. Y. Multifunctional Composite Nanoparticles: Magnetic, Luminescent, and Mesoporous. Chem. Mater. 2006, 18, 5170– 5172, DOI: 10.1021/cm061976z[ACS Full Text], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVGmsb%252FO&md5=1e2ee625914562002680df1526310833Multifunctional composite nanoparticles: magnetic, luminescent, and mesoporousLin, Yu-Shen; Wu, Si-Han; Hung, Yann; Chou, Yi-Hsin; Chang, Chen; Lin, Meng-Liang; Tsai, Chih-Pin; Mou, Chung-YuanChemistry of Materials (2006), 18 (22), 5170-5172CODEN: CMATEX; ISSN:0897-4756. (American Chemical Society)A new strategy for synthesis of uniform magnetic/luminescent functional mesoporous silica nanoparticles with well-ordered porous structure and good aq. dispersity have been developed. The potential in biol. application have been evaluated. Preliminary results in the cell uptake expts. was shown.291Slowing, I. I.; Vivero-Escoto, J. L.; Wu, C. W.; Lin, V. S. Y. Mesoporous Silica Nanoparticles as Controlled Release Drug Delivery and Gene Transfection Carriers. Adv. Drug Delivery Rev. 2008, 60, 1278– 1288, DOI: 10.1016/j.addr.2008.03.012[Crossref], [PubMed], [CAS], Google Scholar291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosVOnsrg%253D&md5=29e5282dd605da1070e8db179d012fafMesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriersSlowing, Igor I.; Vivero-Escoto, Juan L.; Wu, Chia-Wen; Lin, Victor S.-Y.Advanced Drug Delivery Reviews (2008), 60 (11), 1278-1288CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)A review. In this review, we highlight the recent research developments of a series of surface-functionalized mesoporous silica nanoparticle (MSN) materials as efficient drug delivery carriers. The synthesis of this type of MSN materials is described along with the current methods for controlling the structural properties and chem. functionalization for biotechnol. and biomedical applications. We summarized the advantages of using MSN for several drug delivery applications. The recent investigations of the biocompatibility of MSN in vitro are discussed. We also describe the exciting progress on using MSN to penetrate various cell membranes in animal and plant cells. The novel concept of gatekeeping is introduced and applied to the design of a variety of stimuli-responsive nanodevices. We envision that these MSN-based systems have a great potential for a variety of drug delivery applications, such as the site-specific delivery and intracellular controlled release of drugs, genes, and other therapeutic agents.292Tsai, C. P.; Hung, Y.; Chou, Y. H.; Huang, D. M.; Hsiao, J. K.; Chang, C.; Chen, Y. C.; Mou, C. Y. High-Contrast Paramagnetic Fluorescent Mesoporous Silica Nanorods as a Multifunctional Cell-Imaging Probe. Small 2008, 4, 186– 191, DOI: 10.1002/smll.200700457[Crossref], [PubMed], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXisFSksro%253D&md5=25b254cbf8dd2bca9643eb632e640483High-contrast paramagnetic fluorescent mesoporous silica nanorods as a multifunctional cell-imaging probeTsai, Chih-Pin; Hung, Yann; Chou, Yi-Hsin; Huang, Dong-Ming; Hsiao, Jong-Kai; Chang, Chen; Chen, Yao-Chang; Mou, Chung-YuanSmall (2008), 4 (2), 186-191CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)A real contrast, multifunctional fluorescent and paramagnetic mesoporous silica nanorods can be used to label both phagocytic and nonphagocytotic cells. The cells can be detected simultaneously by a fluorescence technique and the T1- or T2-weighted modes of magnetic resonance imaging (see picture).293Popat, A.; Hartono, S. B.; Stahr, F.; Liu, J.; Qiao, S. Z.; Lu, G. Q. Mesoporous Silica Nanoparticles for Bioadsorption, Enzyme Immobilisation, and Delivery Carriers. Nanoscale 2011, 3, 2801– 2818, DOI: 10.1039/c1nr10224a[Crossref], [PubMed], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptVahsLk%253D&md5=60822a6c7735a23c91e8ffdf72bb1920Mesoporous silica nanoparticles for bioadsorption, enzyme immobilisation, and delivery carriersPopat, Amirali; Hartono, Sandy Budi; Stahr, Frances; Liu, Jian; Qiao, Shi Zhang; Lu, Gao QingNanoscale (2011), 3 (7), 2801-2818CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)A review. Mesoporous silica nanoparticles (MSNs) provide a non-invasive and biocompatible delivery platform for a broad range of applications in therapeutics, pharmaceuticals and diagnosis. The creation of smart, stimuli-responsive systems that respond to subtle changes in the local cellular environment are likely to yield long term solns. to many of the current drug/gene/DNA/RNA delivery problems. In addn., MSNs have proven to be promising supports for enzyme immobilization, enabling the enzymes to retain their activity, affording them greater potential for wide applications in biocatalysis and energy. This review provides a comprehensive summary of the advances made in the last decade and a future outlook on possible applications of MSNs as nanocontainers for storage and delivery of biomols. The authors discuss some of the important factors affecting the adsorption and release of biomols. in MSNs and review of the cytotoxicity aspects of such nanomaterials. The review also highlights some promising work on enzyme immobilization using mesoporous silica nanoparticles.294Chouikrat, R.; Seve, A.; Vanderesse, R.; Benachour, H.; Barberi-Heyob, M.; Richeter, S.; Raehm, L.; Durand, J.-O.; Verelst, M.; Frochot, C. Non Polymeric Nanoparticles for Photodynamic Therapy Applications: Recent Developments. Curr. Med. Chem. 2012, 19, 781– 792, DOI: 10.2174/092986712799034897[Crossref], [PubMed], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xislelu7w%253D&md5=3e8e004cb6673dc2f2c9becbc97db9b2Non polymeric nanoparticles for photodynamic therapy applications: recent developmentsChouikrat, R.; Seve, A.; Vanderesse, R.; Benachour, H.; Barberi-Heyob, M.; Richeter, S.; Raehm, L.; Durand, J.-O.; Verelst, M.; Frochot, C.Current Medicinal Chemistry (2012), 19 (6), 781-792CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. Photodynamic therapy has emerged as an alternative to chemotherapy and radiotherapy for cancer treatment. Nanoparticles have recently been proposed as effective carriers for photosensitizers. Depending on their chem. compn., these can be used for diagnosis and therapy due to the selective accumulation of the photosensitizer in cancer cells in vitro or in tumors in vivo. Multifunctional nanoplatforms combining several applications within the same nano-object emerge as potential important theranostic tools. This review, based on the chem. nature of the nanoparticles will discuss recent advances in the area of non polymeric nanoparticles for photodynamic therapy applications.295Lucky, S. S.; Soo, K. C.; Zhang, Y. Nanoparticles in Photodynamic Therapy. Chem. Rev. 2015, 115, 1990– 2042, DOI: 10.1021/cr5004198[ACS Full Text], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFCms70%253D&md5=7ab133bd9468b25ea92f45e5a55738c1Nanoparticles in Photodynamic TherapyLucky, Sasidharan Swarnalatha; Soo, Khee Chee; Zhang, YongChemical Reviews (Washington, DC, United States) (2015), 115 (4), 1990-2042CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review of use of nanoparticles in photodynamic therapy in treatment of cancer. Topics covered include principles of photodynamic therapy; mechanisms of tumor cell killing by photodynamic therapy; photosensitizers; types of nanoparticles used in photodynamic therapy; nanoparticles as down-converting photosensitizers; and nanoparticles as energy transducers.296Piao, Y.; Burns, A.; Kim, J.; Wiesner, U.; Hyeon, T. Designed Fabrication of Silica-Based Nanostructured Particle Systems for Nanomedicine Applications. Adv. Funct. Mater. 2008, 18, 3745– 3758, DOI: 10.1002/adfm.200800731[Crossref], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXitlGl&md5=7984ae006d53aa0d8902e0fe0d38c8f2Designed fabrication of silica-based nanostructured particle systems for nanomedicine applicationsPiao, Yuanzhe; Burns, Andrew; Kim, Jaeyun; Wiesner, Ulrich; Hyeon, TaeghwanAdvanced Functional Materials (2008), 18 (23), 3745-3758CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Suitably integrating multiple nanomaterials into nanostructured particle systems with specific combinations of properties has recently attracted significant attention in the research community. In particular, numerous particle systems were designed and fabricated by integrating diverse materials with monodispersed silica nanoparticles. One or more distinct nanomaterials can be assembled on, encapsulated within, or integrated both inside and on the surface of silica nanoparticles using different chemistries and techniques to create multifunctional nanosystems. Research on these particle systems for biomedical applications has progressed rapidly during recent years due to the synergistic advantages of these complexes compared to the use of single components. This feature article surveys recent research progress on the fabrication strategies of these nanoparticle systems and their applications to medical diagnostics and therapy, thereby paving the way for the emerging field of nanomedicine.297Ohulchanskyy, T. Y.; Roy, I.; Goswami, L. N.; Chen, Y.; Bergey, E. J.; Pandey, R. K.; Oseroff, A. R.; Prasad, P. N. Organically Modified Silica Nanoparticles With Covalently Incorporated Photosensitizer for Photodynamic Therapy of Cancer. Nano Lett. 2007, 7, 2835– 2842, DOI: 10.1021/nl0714637[ACS Full Text], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsVKntrc%253D&md5=aebde26a31eef628ff9752cb2a0fc1d7Organically Modified Silica Nanoparticles with Covalently Incorporated Photosensitizer for Photodynamic Therapy of CancerOhulchanskyy, Tymish Y.; Roy, Indrajit; Goswami, Lalit N.; Chen, Yihui; Bergey, Earl J.; Pandey, Ravindra K.; Oseroff, Allan R.; Prasad, Paras N.Nano Letters (2007), 7 (9), 2835-2842CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)The authors report a novel nanoformulation of a photosensitizer (PS), for photodynamic therapy (PDT) of cancer, where the PS mols. are covalently incorporated into organically modified silica (ORMOSIL) nanoparticles. The authors found that the covalently incorporated PS mols. retained their spectroscopic and functional properties and could robustly generate cytotoxic singlet oxygen mols. upon photoirradn. The synthesized nanoparticles are of ultralow size (∼20 nm) and are highly monodispersed and stable in aq. suspension. The advantage offered by this covalently linked nanofabrication is that the drug is not released during systemic circulation, which is often a problem with phys. encapsulation. These nanoparticles are also avidly uptaken by tumor cells in vitro and demonstrate phototoxic action, thereby highlighting their potential in diagnosis and PDT of cancer.298Tang, W.; Xu, H.; Kopelman, R.; A. Philbert, M. Photodynamic Characterization and In Vitro Application of Methylene Blue-Containing Nanoparticle Platforms. Photochem. Photobiol. 2005, 81, 242, DOI: 10.1562/2004-05-24-RA-176.1[Crossref], [PubMed], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjslGmsL4%253D&md5=686cf523c6d67f6135397b9298a523fcPhotodynamic characterization and in vitro application of methylene blue-containing nanoparticle platformsTang, Wei; Xu, Hao; Kopelman, Raoul; Philbert, Martin A.Photochemistry and Photobiology (2005), 81 (Mar./Apr.), 242-249CODEN: PHCBAP; ISSN:0031-8655. (American Society for Photobiology)This article presents the development and characterization of nanoparticles loaded with methylene blue (MB), which are designed to be administered to tumor cells externally and deliver singlet oxygen (1O2) for photodynamic therapy (PDT), i.e. cell kill via oxidative stress to the membrane. We demonstrated the encapsulation of MB, a photosensitizer (PS), in three types of sub-200 nm nanoparticles, composed of polyacrylamide, sol-gel silica and organically modified silicate (ORMOSIL), resp. Induced by light irradn., the entrapped MB generated 1O2, and the produced 1O2 was measured quant. with anthracene-9,10-dipropionic acid, disodium salt, to compare the effects of different matrixes on 1O2 delivery. Among these three different kinds of nanoparticles, the polyacrylamide nanoparticles showed the most efficient delivery of 1O2, but its loading of MB was low. In contrast, the sol-gel nanoparticles had the best MB loading but the least efficient 1O2 delivery. In addn. to investigating the matrix effects, a preliminary in vitro PDT study using the MB-loaded polyacrylamide nanoparticles was conducted on rat C6 glioma tumor cells with pos. photodynamic results. The encapsulation of MB in nanoparticles should diminish the interaction of this PS with the biol. milieu, thus facilitating its systemic administration. Furthermore, the concept of the drug-delivering nanoparticles has been extended to a new type of dynamic nanoplatform (DNP) that only delivers 1O2. This DNP could also be used as a targeted multifunctional platform for combined diagnostics and therapy of cancer.299Biju, V. Chemical Modifications and Bioconjugate Reactions of Nanomaterials for Sensing, Imaging, Drug Delivery and Therapy. Chem. Soc. Rev. 2014, 43, 744– 764, DOI: 10.1039/C3CS60273G[Crossref], [PubMed], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlvFCmsA%253D%253D&md5=215ad49a37d22902f02fa80fcea5f349Chemical modifications and bioconjugate reactions of nanomaterials for sensing, imaging, drug delivery and therapyBiju, VasudevanpillaiChemical Society Reviews (2014), 43 (3), 744-764CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. As prepd. nanomaterials of metals, semiconductors, polymers and carbon often need surface modifications such as ligand exchange, and chem. and bioconjugate reactions for various biosensor, bioanal., bioimaging, drug delivery and therapeutic applications. Such surface modifications help us to control the physico-chem., toxicol. and pharmacol. properties of nanomaterials. Furthermore, introduction of various reactive functional groups on the surface of nanomaterials allows us to conjugate a spectrum of contrast agents, antibodies, peptides, ligands, drugs and genes, and construct multifunctional and hybrid nanomaterials for the targeted imaging and treatment of cancers. This tutorial review is intended to provide an introduction to newcomers about how chem. and bioconjugate reactions transform the surface of nanomaterials such as silica nanoparticles, gold nanoparticles, gold quantum clusters, semiconductor quantum dots, carbon nanotubes, fullerene and graphene, and accordingly formulate them for applications such as biosensing, bioimaging, drug and gene delivery, chemotherapy, photodynamic therapy and photothermal therapy. Nonetheless, controversial reports and our growing concerns about toxicity and pharmacokinetics of nanomaterials suggest the need for not only rigorous in vivo expts. in animal models but also novel nanomaterials for practical applications in the clin. settings. Further reading of original and review articles cited herein is necessary to buildup in-depth knowledge about the chem., bioconjugate chem. and biol. applications of individual nanomaterials.300Castilho, M. L.; Vieira, L. S.; Campos, A. P. C.; Achete, C. A.; Cardoso, M. A. G.; Raniero, L. The Efficiency Analysis of Gold Nanoprobes by FT-IR Spectroscopy Applied to the Non-Cross-Linking Colorimetric Detection of Paracoccidioides Brasiliensis. Sens. Actuators, B 2015, 215, 258– 265, DOI: 10.1016/j.snb.2015.03.052[Crossref], [CAS], Google Scholar300https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmt1yqsbc%253D&md5=6b99d039c05505513573b08c3e3733d2The efficiency analysis of gold nanoprobes by FT-IR spectroscopy applied to the non-cross-linking colorimetric detection of Paracoccidioides brasiliensisCastilho, M. L.; Vieira, L. S.; Campos, A. P. C.; Achete, C. A.; Cardoso, M. A. G.; Raniero, L.Sensors and Actuators, B: Chemical (2015), 215 (), 258-265CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)Nanodiagnostics have become an important tool for the development of new methods for clin. and lab. diagnosis. Non-crosslinking colorimetric detection is a promising technique using thiol-modified oligonucleotides (probes) functionalized gold nanoparticles. The nanoprobes allow the detection of a specific sequence of complementary DNA (cDNA) for a well-characterized antigenic protein 27 kDa (p27), which is capable of reacting with the serum of 91% of the patients infected with fungus Paracoccidioides brasiliensis the etiol. agent of Paracoccidioidomycosis. In this work nanoprobe groups were synthesized with final concn. of 33.6 nM, 66.1 nM and 128.1 nM thiolated oligonucleotides. To evaluate the efficiency of the nanoprobes Fourier Transform IR (FT-IR) was used to identify the functional groups of the probe and its bond to the gold nanoparticle. The region between 200 cm-1 and 280 cm-1 corresponds to the Au-S bond, which is a detg. factor for the efficiency of colorimetric detection. The FT-IR results are corroborated with images taken with the Transmission Electron Microscopy (TEM) technique, where the difference between functionalization groups is evident. Considering these aspects, the present work aims to develop a new mol. diagnosis of the fungus Paracoccidioides brasiliensis by non-crosslinking colorimetric detection method using a probe from p27 antigenic cDNA sequence. The non-crosslinking colorimetric diagnostic test possesses 84.4% sensitivity and 81.2% specificity, and may be implemented as clin. diagnosis with simple execution and reasonable cost to effectively detect of Paracoccidioides brasiliensis.301Khaing Oo, M. K.; Yang, Y.; Hu, Y.; Gomez, M.; Du, H.; Wang, H. Gold Nanoparticle-Enhanced and Size-Dependent Generation of Reactive Oxygen Species from Protoporphyrin IX. ACS Nano 2012, 6, 1939– 1947, DOI: 10.1021/nn300327c[ACS Full Text], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjt1Srt7w%253D&md5=c3707a9f91a0fc17975f44278bb13762Gold Nanoparticle-Enhanced and Size-Dependent Generation of Reactive Oxygen Species from Protoporphyrin IXKhaing Oo, Maung Kyaw; Yang, Yamin; Hu, Yue; Gomez, Maria; Du, Henry; Wang, HongjunACS Nano (2012), 6 (3), 1939-1947CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Photosensitizer, protoporphyrin IX (PpIX), was conjugated with Au nanoparticles (Au NPs) of 19, 66, and 106 nm diam. to study the size-dependent enhancement of reactive oxygen species (ROS) formation enabled by Au NPs. The ROS enhancement ratio is detd. to be 1:2.56:4.72 in order of increasing Au NP size, in general agreement with theor. calcd. field enhancement to the fourth power. The convergence of the exptl. and simulated results suggests that Au NP-enhanced and size-dependent ROS formation can be attributed directly to the localized electromagnetic field as a result of surface plasmonic resonance of Au NPs under light irradn. In vitro study on the ROS formation enabled by PpIX-conjugated Au NPs in human breast cancer cells (MDA-MB-231) revealed the similar size-dependent enhancement of intracellular ROS formation, while the enhancement greatly depended on cellular uptake of Au NPs. Cellular photodynamic therapy revealed that cell destruction significantly increased in the presence of Au NPs. Compared to the untreated control (0% destruction), 22.6% cell destruction was seen in the PpIX alone group and more than 50% cell destruction was obtained for all PpIX-conjugated Au NPs. The 66 nm Au NPs yielded the highest cell destruction, consistent with the highest cellular uptake and highest ROS formation. Clearly, the complex cellular environment, size-dependent cellular uptake of Au NPs, and ROS generations are vital contributors to the overall cellular PDT efficacy.302Amini, S. M.; Kharrazi, S.; Hadizadeh, M.; Fateh, M.; Saber, R. Effect of Gold Nanoparticles on Photodynamic Efficiency of 5-Aminolevolenic Acid Photosensitiser in Epidermal Carcinoma Cell Line: An In Vitro Study. IET Nanobiotechnol. 2013, 7, 151– 156, DOI: 10.1049/iet-nbt.2013.0021[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFWks7vK&md5=cbdc93606ef3fe79524a71f7550df11dEffect of gold nanoparticles on photodynamic efficiency of 5-aminolevolenic acid photosensitiser in epidermal carcinoma cell line: an in vitro studyAmini, Seyed Mohammad; Kharrazi, Sharmin; Hadizadeh, Mahnaz; Fateh, Mohsen; Saber, RezaIET Nanobiotechnology (2013), 7 (4), 151-156CODEN: INEACX; ISSN:1751-8741. (Institution of Engineering and Technology)In the recent years, enhanced functionality of treatment systems based on nanostructures has attracted a lot of interest. Photodynamic therapy (PDT) is one such treatment method. Here, the authors report the results of the investigations on synthesis and characterization of gold nanoparticles (GNPs) and their application in PDT along with 5-aminolevolenic acid (5-ALA) (as photosensitizer) with no conjugation. Three sizes of GNPs were synthesized and their cytotoxicity was investigated by using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay on epidermal carcinoma cell line. The results showed that the PDT efficiency of ALA increased in presence of GNPs. This effect was more considerable for 4 nm particles.303Pasparakis, G. Light-Induced Generation of Singlet Oxygen by Naked Gold Nanoparticles and Its Implications to Cancer Cell Phototherapy. Small 2013, 9, 4130– 4134, DOI: 10.1002/smll.201301365[Crossref], [PubMed], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVaktbbF&md5=99a30f76c00b8eb43bc463b156a245cfLight-Induced Generation of Singlet Oxygen by Naked Gold Nanoparticles and its Implications to Cancer Cell PhototherapyPasparakis, GeorgeSmall (2013), 9 (24), 4130-4134CODEN: SMALBC; ISSN:1613-6810. (Wiley-VCH Verlag GmbH & Co. KGaA)Gold nanoparticles were found to generate singlet oxygen after irradn. with pulse laser. Their potential use in cancer phototherapy is discused.304Sherwani, M. A.; Tufail, S.; Khan, A. A.; Owais, M. Gold Nanoparticle-Photosensitizer Conjugate Based Photodynamic Inactivation of Biofilm Producing Cells: Potential for Treatment of C. Albicans Infection in BALB/c Mice. PLoS One 2015, 10, e0131684, DOI: 10.1371/journal.pone.0131684305Penon, O.; Marín, M. J.; Russell, D. A.; Pérez-García, L. Water Soluble, Multifunctional Antibody-Porphyrin Gold Nanoparticles for Targeted Photodynamic Therapy. J. Colloid Interface Sci. 2017, 496, 100– 110, DOI: 10.1016/j.jcis.2017.02.006[Crossref], [PubMed], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXivVKmt7o%253D&md5=ca69d57f51d0720a8318eab71cd099a5Water soluble, multifunctional antibody-porphyrin gold nanoparticles for targeted photodynamic therapyPenon, Oriol; Marin, Maria J.; Russell, David A.; Perez-Garcia, LluisaJournal of Colloid and Interface Science (2017), 496 (), 100-110CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)Photodynamic therapy (PDT) is a treatment of cancer by which tumor cells are destroyed using reactive oxygen species produced by photosensitizers following activation with visible or near IR light. Successful PDT depends on the soly. and the targeting ability of the photosensitizers. In this work, the synthesis of a porphyrin-based water sol. nanoparticle conjugate contg. a targeting agent that recognizes the erbB2 receptor overexpressed on the surface of particular cancer cells is reported. The nanoparticle conjugates were synthesized following two different protocols, viz. a biphasic and a monophasic method, with the aim to det. which method yielded the optimal nanosystem for potential PDT applications. The nanoparticles were characterized using UV-Vis absorption and fluorescence spectroscopies together with transmission electron microscopy and zeta potential measurements; and their ability to produce singlet oxygen following irradn. was investigated following the decay in absorption of a singlet oxygen probe. The nanoparticles synthesized using the monophasic method were shown to produce the highest amt. of singlet oxygen and were further functionalized with anti-erbB2 antibody to target the erbB2 receptors expressed on the surface of SK-BR-3 human breast cancer cells. The water sol., antibody-porphyrin nanoparticle conjugates were shown to elicit targeted PDT of the breast cancer cells.306Basu, S.; Alavi, A. SPECT-CT and PET-CT in Oncology - An Overview. Curr. Med. Imaging Rev. 2011, 7, 202– 209, DOI: 10.2174/157340511796411168307Chopra, A.; Shan, L.; Eckelman, W. C.; Leung, K.; Menkens, A. E. Important Parameters to Consider for the Characterization of PET and SPECT Imaging Probes. Nucl. Med. 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Biol. 2003, 7, 626– 634, DOI: 10.1016/j.cbpa.2003.08.007[Crossref], [PubMed], [CAS], Google Scholar308https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXot12hsL0%253D&md5=6d10740d915f2372ac60a811c357ddb5In vivo near-infrared fluorescence imagingFrangioni, John V.Current Opinion in Chemical Biology (2003), 7 (5), 626-634CODEN: COCBF4; ISSN:1367-5931. (Elsevier Science Ltd.)A review. Photon penetration into living tissue is highly dependent on the absorption and scattering properties of tissue components. The near-IR region of the spectrum offers certain advantages for photon penetration, and both org. and inorg. fluorescence contrast agents are now available for chem. conjugation to targeting mols. This review focuses on those parameters that affect image signal and background during in vivo imaging with near-IR light and exogenous contrast agents. Recent examples of in vivo near-IR fluorescence imaging of animals and humans are presented, including imaging of normal and diseased vasculature, tissue perfusion, protease activity, hydroxyapatite and cancer.309Ntziachristos, V.; Bremer, C.; Weissleder, R. Fluorescence Imaging With Near-Infrared Light: New Technological Advances That Enable in Vivo Molecular Imaging. Eur. Radiol. 2003, 13, 195– 208, DOI: 10.1007/s00330-002-1524-x[Crossref], [PubMed], [CAS], Google Scholar309https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s%252FjtlKgtg%253D%253D&md5=4a782489ce6a4bf19358d7004cc9c592Fluorescence imaging with near-infrared light: new technological advances that enable in vivo molecular imagingNtziachristos Vasilis; Bremer Christoph; Weissleder RalphEuropean radiology (2003), 13 (1), 195-208 ISSN:0938-7994.A recent development in biomedical imaging is the non-invasive mapping of molecular events in intact tissues using fluorescence. Underpinning to this development is the discovery of bio-compatible, specific fluorescent probes and proteins and the development of highly sensitive imaging technologies for in vivo fluorescent detection. Of particular interest are fluorochromes that emit in the near infrared (NIR), a spectral window, whereas hemoglobin and water absorb minimally so as to allow photons to penetrate for several centimetres in tissue. In this review article we concentrate on optical imaging technologies used for non-invasive imaging of the distribution of such probes. We illuminate the advantages and limitations of simple photographic methods and turn our attention to fluorescence-mediated molecular tomography (FMT), a technique that can three-dimensionally image gene expression by resolving fluorescence activation in deep tissues. We describe theoretical specifics, and we provide insight into its in vivo capacity and the sensitivity achieved. Finally, we discuss its clinical feasibility.310Peng, C.-L.; Shih, Y.-H.; Lee, P.-C.; Hsieh, T. M.-H.; Luo, T.-Y.; Shieh, M.-J. Multimodal Image-Guided Photothermal Therapy Mediated by 188Re-Labeled Micelles Containing a Cyanine-Type Photosensitizer. ACS Nano 2011, 5, 5594– 5607, DOI: 10.1021/nn201100m[ACS Full Text], [CAS], Google Scholar310https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnvVarsr4%253D&md5=bf19fd5e33a7b667f9bfea57fa4aa916Multimodal Image-Guided Photothermal Therapy Mediated by 188Re-Labeled Micelles Containing a Cyanine-Type PhotosensitizerPeng, Cheng-Liang; Shih, Ying-Hsia; Lee, Pei-Chi; Hsieh, Thomas Mon-Hsian; Luo, Tsai-Yueh; Shieh, Ming-JiumACS Nano (2011), 5 (7), 5594-5607CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Multifunctional micelles loaded with the near-IR (NIR) dye and labeled with the radionuclide rhenium-188 (188Re) have been developed to provide multimodalities for NIR fluorescence and nuclear imaging and for photothermal therapy (PTT) of cancer. The NIR dye, IR-780 iodide, allowed the micelles to have dual functions in cancer NIR imaging and PTT. The 188Re-labeled IR-780 micelles enabled imaging by NIR fluorescence and by microSPECT to guide the delivery of drugs and to monitor in real-time the tumor accumulation, intratumoral distribution, and kinetics of drug release, which serve as a basis of specific photothermal injury to the targeted tissue. We also investigated the biodistribution, generation of heat, and photothermal cancer ablation of IR-780 micelles of both in vitro and in vivo xenografts. Histopathol. obsd. irreversible tissue damage, such as necrotic features, decreased cell proliferation, increased apoptosis of cells, and increased expression of heat shock proteins in the PTT-treated tumors. The 188Re-labeled IR-780 micelles offer multifunctional modalities for NIR fluorescence and nuclear imaging and for PTT of cancer.311Shen, X.; Li, L.; Wu, H.; Yao, S. Q.; Xu, Q. H. Photosensitizer-Doped Conjugated Polymer Nanoparticles for Simultaneous Two-Photon Imaging and Two-Photon Photodynamic Therapy in Living Cells. Nanoscale 2011, 3, 5140– 5146, DOI: 10.1039/c1nr11104c[Crossref], [PubMed], [CAS], Google Scholar311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFCmtL7M&md5=83ad09b7622310c1e1476af43392ba97Photosensitizer-doped conjugated polymer nanoparticles for simultaneous two-photon imaging and two-photon photodynamic therapy in living cellsShen, Xiaoqin; Li, Lin; Wu, Hao; Yao, Shao Q.; Xu, Qing-HuaNanoscale (2011), 3 (12), 5140-5146CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)Photosensitizer doped conjugated polymer nanoparticles have been prepd. by incorporating polyoxyethylene nonylphenylether (CO-520) into the nanoparticles using a re-pptn. method. The conjugated polymer, poly[9,9-dibromohexylfluorene-2,7-ylenethylene-alt-1,4-(2,5-dimethoxy)phenylene] (PFEMO), was used as the host matrix to disperse tetraphenylporphyrin (TPP) and an energy donor to enhance the two-photon excitation properties of TPP. These CO-520 incorporated, TPP-doped PFEMO nanoparticles are stable and have low cytotoxicity in the dark. The TPP emission of the nanoparticles was found to be enhanced by about 20 times by PFEMO under two-photon excitation. The nanoparticles showed significantly enhanced two-photon excitation singlet oxygen generation efficiency and two-photon photodynamic therapy activity in cancer cells. These composite nanoparticles display features required for ideal photosensitizers, such as low cytotoxicity in the dark and efficient two-photon photodynamic activity under laser radiation. In addn., these novel nano-photosensitizers allow simultaneous in vivo monitoring by two-photon fluorescence imaging during two-photon photodynamic treatment. These photosensitizer-doped conjugated polymer nanoparticles can act as novel photosensitizing agents for two-photon photodynamic therapy and related applications.312Tian, J.; Ding, L.; Xu, H. J.; Shen, Z.; Ju, H.; Jia, L.; Bao, L.; Yu, J. S. Cell-Specific and PH-Activatable Rubyrin-Loaded Nanoparticles for Highly Selective Near-Infrared Photodynamic Therapy Against Cancer. J. Am. Chem. Soc. 2013, 135, 18850– 18858, DOI: 10.1021/ja408286k[ACS Full Text], [CAS], Google Scholar312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVKjt77M&md5=57b349edb81bf882eb869aac21bf9586Cell-Specific and pH-Activatable Rubyrin-Loaded Nanoparticles for Highly Selective Near-Infrared Photodynamic Therapy against CancerTian, Jiangwei; Ding, Lin; Xu, Hai-Jun; Shen, Zhen; Ju, Huangxian; Jia, Li; Bao, Lei; Yu, Jun-ShengJournal of the American Chemical Society (2013), 135 (50), 18850-18858CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Spatiotemporal control of singlet oxygen (1O2) release is a major challenge for photodynamic therapy (PDT) against cancer with high therapeutic efficacy and min. side effects. Here a selenium-rubyrin (NMe2Se4N2)-loaded nanoparticle functionalized with folate (FA) was designed and synthesized as an acidic pH-activatable targeted photosensitizer. The nanoparticles could specifically recognize cancer cells via the FA-FA receptor binding and were selectively taken up by cancer cells via receptor-mediated endocytosis to enter lysosomes, in which NMe2Se4N2 was activated to produce 1O2. The pH-controllable release of 1O2 specially damaged the lysosomes and thus killed cancer cells in a lysosome-assocd. pathway. The introduction of selenium into the rubyrin core enhanced the 1O2 generation efficiency due to the heavy atom effect, and the substitution of dimethylaminophenyl moiety at meso-position led to the pH-controllable activation of NMe2Se4N2. Under near-IR (NIR) irradn., NMe2Se4N2 possessed high singlet oxygen quantum yield (ΦΔ) at an acidic pH (ΦΔ = 0.69 at pH 5.0 at 635 nm) and could be deactivated at physiol. pH (ΦΔ = 0.06 at pH 7.4 at 635 nm). The subcellular location-confined pH-activatable photosensitization at NIR region and the cancer cell-targeting feature led to excellent capability to selectively kill cancer cells and prevent the damage to normal cells, which greatly lowered the side effects. Through i.v. injection of FA-NMe2Se4N2 nanoparticles in tumor-bearing mice, tumor elimination was obsd. after NIR irradn. This work presents a new paradigm for specific PDT against cancer and provides a new avenue for prepn. of highly efficient photosensitizers.313Tsai, H. C.; Tsai, C. H.; Lin, S. Y.; Jhang, C. R.; Chiang, Y. S.; Hsiue, G. H. Stimulated Release of Photosensitizers from Graft and Diblock Micelles for Photodynamic Therapy. Biomaterials 2012, 33, 1827– 1837, DOI: 10.1016/j.biomaterials.2011.11.014[Crossref], [PubMed], [CAS], Google Scholar313https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1ejtL7K&md5=da5136aa6bc14848a12c0f682e608ac9Stimulated release of photosensitizers from graft and diblock micelles for photodynamic therapyTsai, Hsieh-Chih; Tsai, Cheng-Hung; Lin, Shuian-Yin; Jhang, Chang-Rong; Chiang, Yung-Sheng; Hsiue, Ging-HoBiomaterials (2012), 33 (6), 1827-1837CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)To understand the effect of photosensitizer (PS) release from graft copolymer based micelles in photodynamic therapy (PDT), the two pH-sensitive and non-pH-sensitive graft copolymers, (poly(N-vinylcaprolactam)-g-poly(D,L-lactide) and poly(N-vinylcaprolactam-co-N-vinyl imidazole)-g-poly(D,L-lactide)), were synthesized and utilized for the encapsulation of protoporphyrin IX (PPIX) for in vitro and in vivo PDT studies. Photochem. internalization (PCI) was utilized to study the localization of pH- and non-pH-sensitive micelles uptake in the lysosome. After non-toxic light treatment, PPIX was found in the nucleus with pH-sensitive micelles, while PPIX was still localized in the lysosomal organism with the non-pH-sensitive micelles, as obsd. by confocal microscopy. Because the formation of singlet oxygen was obsd. for the block and graft micelles, dramatic differences in the cell viability could be ascribed to the damage occurring at the region where the PPIX was located. An in vivo study revealed that PPIX-loaded graft and diblock micelles presented prolonged blood circulation and enhanced tumor targeting ability. The PPIX released from g-CIM micelles on tumor site was further proved by ex vivo confocal image. In addn., non-pH-sensitive micelle-treated mice showed a better repression of tumor growth than PPIX-treated mice, which was likely due to the larger amt. of PS localized in the tumor region still exhibiting therapeutic effects. Finally, effective PDT-induced inhibition of tumor growth was found in pH-sensitive micelle-treated mice. This work provides insight into PS-loaded graft and diblock micelles for the PDT of tumors.314Kim, H.; Mun, S.; Choi, Y. Photosensitizer-Conjugated Polymeric Nanoparticles for Redox-Responsive Fluorescence Imaging and Photodynamic Therapy. J. Mater. Chem. B 2013, 1, 429– 431, DOI: 10.1039/C2TB00287F[Crossref], [PubMed], [CAS], Google Scholar314https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVyms7bP&md5=730e3fedd75309c0febd005cbd7cab8bPhotosensitizer-conjugated polymeric nanoparticles for redox-responsive fluorescence imaging and photodynamic therapyKim, Hyunjin; Mun, Saehun; Choi, YongdooJournal of Materials Chemistry B: Materials for Biology and Medicine (2013), 1 (4), 429-431CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)Photosensitizers conjugated with hyaluronic acid via disulfide linkers were developed for biol. activatable near-IR fluorescence imaging and photodynamic therapy. The nanoparticles prepd. from the conjugate are nonfluorescent and nonphototoxic in their native state, but become highly fluorescent and phototoxic in response to reductive agents inside cancer cells.315Wang, C.; Cheng, L.; Liu, Y.; Wang, X.; Ma, X.; Deng, Z.; Li, Y.; Liu, Z. Imaging-Guided PH-Sensitive Photodynamic Therapy Using Charge Reversible Upconversion Nanoparticles Under Near -Infrared Light. Adv. Funct. Mater. 2013, 23, 3077– 3086, DOI: 10.1002/adfm.201202992[Crossref], [CAS], Google Scholar315https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFSqu78%253D&md5=6f99f4013e5a376db12d0713dd91799eImaging-Guided pH-Sensitive Photodynamic Therapy Using Charge Reversible Upconversion Nanoparticles under Near-Infrared LightWang, Chao; Cheng, Liang; Liu, Yumeng; Wang, Xiaojing; Ma, Xinxing; Deng, Zhaoyi; Li, Yonggang; Liu, ZhuangAdvanced Functional Materials (2013), 23 (24), 3077-3086CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)Photodynamic therapy (PDT) based on upconversion nanoparticles (UCNPs) can effectively destroy cancer cells under tissue-penetrating near-IR light (NIR) light. Herein, we synthesize manganese (Mn2+)-doped UCNPs with strong red light emission at ca. 660 nm under 980 nm NIR excitation to activate Chlorin e6 (Ce6), producing singlet oxygen (1O2) to kill cancer cells. A layer-by-layer (LbL) self-assembly strategy is employed to load multiple layers of Ce6 conjugated polymers onto UCNPs via electrostatic interactions. UCNPs with two layers of Ce6 loading ([email protected]) are found to be optimal in terms of Ce6 loading and 1O2 generation. By further coating [email protected] with an outer layer of charge-reversible polymer contg. dimethylmaleic acid (DMMA) groups and polyethylene glycol (PEG) chains, we obtain a [email protected] nanocomplex, the surface of which is neg. charged and PEG coated under pH 7.4; this could be converted to have a pos. charged naked surface at pH 6.8, significantly enhancing cell internalization of nanoparticles and increasing in vitro NIR-induced PDT efficacy. We then utilize the intrinsic optical and paramagnetic properties of Mn2+-doped UCNPs for in vivo dual modal imaging, and uncover an enhanced retention of [email protected] inside the tumor after intratumoral injection, owing to the slightly acidic tumor microenvironment. Consequently, a significantly improved in vivo PDT therapeutic effect is achieved using our charge-reversible [email protected] nanoparticles. Finally, we further demonstrate the remarkably enhanced tumor-homing of these pH-responsive charge-switchable nanoparticles in comparison to a control counterpart without pH sensitivity after systemic i.v. injection. Our results suggest that UCNPs with finely designed surface coatings could serve as smart pH-responsive PDT agents promising in cancer theranostics.316Yoon, H. Y.; Koo, H.; Choi, K. Y.; Lee, S. J.; Kim, K.; Kwon, I. C.; Leary, J. F.; Park, K.; Yuk, S. H.; Park, J. H.; Choi, K. Tumor-Targeting Hyaluronic Acid Nanoparticles for Photodynamic Imaging and Therapy. Biomaterials 2012, 33, 3980– 3989, DOI: 10.1016/j.biomaterials.2012.02.016[Crossref], [PubMed], [CAS], Google Scholar316https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivFWrs7c%253D&md5=a0ccf0320f80ff13519a8e3b1643f9a6Tumor-targeting hyaluronic acid nanoparticles for photodynamic imaging and therapyYoon, Hong Yeol; Koo, Heebeom; Choi, Ki Young; Lee, So Jin; Kim, Kwangmeyung; Kwon, Ick Chan; Leary, James F.; Park, Kinam; Yuk, Soon Hong; Park, Jae Hyung; Choi, KuiwonBiomaterials (2012), 33 (15), 3980-3989CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)Tumor-targeted imaging and therapy have been the challenging issue in the clin. field. Herein, we report tumor-targeting hyaluronic acid nanoparticles (HANPs) as the carrier of the hydrophobic photosensitizer, chlorin e6 (Ce6) for simultaneous photodynamic imaging and therapy. First, self-assembled HANPs were synthesized by chem. conjugation of aminated 5β-cholanic acid, polyethylene glycol (PEG), and black hole quencher3 (BHQ3) to the HA polymers. Second, Ce6 was readily loaded into the HANPs by a simple dialysis method resulting in Ce6-loaded hyaluronic acid nanoparticles (Ce6-HANPs), wherein in the loading efficiency of Ce6 was higher than 80%. The resulting Ce6-HANPs showed stable nano-structure in aq. condition and rapid uptake into tumor cells. In particular Ce6-HANPs were rapidly degraded by hyaluronidases abundant in cytosol of tumor cells, which may enable intracellular release of Ce6 at the tumor tissue. After an i.v. injection into the tumor-bearing mice, Ce6-HANPs could efficiently reach the tumor tissue via the passive targeting mechanism and specifically enter tumor cells through the receptor-mediated endocytosis based on the interactions between HA of nanoparticles and CD44, the HA receptor on the surface of tumor cells. Upon laser irradn., Ce6 which was released from the nanoparticles could generate fluorescence and singlet oxygen inside tumor cells, resulting in effective suppression of tumor growth. Overall, it was demonstrated that Ce6-HANPs could be successfully applied to in vivo photodynamic tumor imaging and therapy simultaneously.317Lee, S. J.; Koo, H.; Jeong, H.; Huh, M. S.; Choi, Y.; Jeong, S. Y.; Byun, Y.; Choi, K.; Kim, K.; Kwon, I. C. Comparative Study of Photosensitizer Loaded and Conjugated Glycol Chitosan Nanoparticles for Cancer Therapy. J. Controlled Release 2011, 152, 21– 29, DOI: 10.1016/j.jconrel.2011.03.027[Crossref], [PubMed], [CAS], Google Scholar317https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmvFyksLc%253D&md5=b8b07ec369efb73defe029216bf9dff0Comparative study of photosensitizer loaded and conjugated glycol chitosan nanoparticles for cancer therapyLee, So Jin; Koo, Heebeom; Jeong, Hayoung; Huh, Myung Sook; Choi, Yongseok; Jeong, Seo Young; Byun, Youngro; Choi, Kuiwon; Kim, Kwangmeyung; Kwon, Ick ChanJournal of Controlled Release (2011), 152 (1), 21-29CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)This study reports that tumor-targeting glycol chitosan nanoparticles with phys. loaded and chem. conjugated photosensitizers can be used in photodynamic therapy (PDT). First, the hydrophobic photosensitizer, chlorin e6 (Ce6), was phys. loaded onto the hydrophobically-modified glycol chitosan nanoparticles (HGC), which were prepd. by self-assembling amphiphilic glycol chitosan-5β-cholanic acid conjugates under aq. conditions. Second, the Ce6s were chem. conjugated to the glycol chitosan polymers, resulting in amphiphilic glycol chitosan-Ce6 conjugates that formed self-assembled nanoparticles in aq. condition. Both Ce6-loaded glycol chitosan nanoparticles (HGC-Ce6) and Ce6-conjugated chitosan nanoparticles (GC-Ce6) had similar av. diams. of 300 to 350 nm, a similar in vitro singlet oxygen generation efficacy under buffer conditions, and a rapid cellular uptake profile in the cell culture system. However, compared to GC-Ce6, HGC-Ce6 showed a burst of drug release in vitro, whereby 65% of phys. loaded drugs were rapidly released from the particles within 6.5 h in the buffer condition. When injected through the tail vein into tumor bearing mice, HGC-Ce6 did not accumulate efficiently in tumor tissue, reflecting the burst in the release of the phys. loaded drug, while GC-Ce6 showed a prolonged circulation profile and a more efficient tumor accumulation, which resulted in high therapeutic efficacy. These comparative studies with drug-loaded and drug-conjugated nanoparticles showed that the photosensitizer-conjugated glycol chitosan nanoparticles with excellent tumor targeting properties have potential for PDT in cancer treatment.318Taratula, O.; Patel, M.; Schumann, C.; Naleway, M. A.; Pang, A. J.; He, H.; Taratula, O. Phthalocyanine-Loaded Graphene Nanoplatform for Imaging-Guided Combinatorial Phototherapy. Int. J. Nanomed. 2015, 10, 2347– 2362, DOI: 10.2147/IJN.S81097[Crossref], [PubMed], [CAS], Google Scholar318https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmvFCjtbc%253D&md5=b98761878a1323794932fcd7ea35b809Phthalocyanine-loaded graphene nanoplatform for imaging-guided combinatorial phototherapyTaratula, Olena; Patel, Mehulkumar; Schumann, Canan; Naleway, Michael A.; Pang, Addison J.; He, Huixin; Taratula, OlehInternational Journal of Nanomedicine (2015), 10 (), 2347-2362CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)We report a novel cancer-targeted nanomedicine platform for imaging and prospect for future treatment of unresected ovarian cancer tumors by intraoperative multimodal phototherapy. To develop the required theranostic system, novel low-oxygen graphene nanosheets were chem. modified with polypropylenimine dendrimers loaded with phthalocyanine (Pc) as a photosensitizer. Such a mol. design prevents fluorescence quenching of the Pc by graphene nanosheets, providing the possibility of fluorescence imaging. Furthermore, the developed nanoplatform was conjugated with poly(ethylene glycol), to improve biocompatibility, and with LH-releasing hormone (LHRH) peptide, for tumor-targeted delivery. Notably, a low-power near-IR (NIR) irradn. of single wavelength was used for both heat generation by the graphene nanosheets (photothermal therapy [PTT]) and for reactive oxygen species (ROS)-prodn. by Pc (photodynamic therapy [PDT]). The combinatorial phototherapy resulted in an enhanced destruction of ovarian cancer cells, with a killing efficacy of 90%-95% at low Pc and low-oxygen graphene dosages, presumably conferring cytotoxicity to the synergistic effects of generated ROS and mild hyperthermia. An animal study confirmed that Pc loaded into the nanoplatform can be employed as a NIR fluorescence agent for imaging-guided drug delivery. Hence, the newly developed Pc-graphene nanoplatform has the significant potential as an effective NIR theranostic probe for imaging and combinatorial phototherapy.319Choi, Y.; Kim, S.; Choi, M.-H.; Ryoo, S.-R.; Park, J.; Min, D.-H.; Kim, B.-S. Photodynamic Therapy: Highly Biocompatible Carbon Nanodots for Simultaneous Bioimaging and Targeted Photodynamic Therapy In Vitro and In Vivo. Adv. Funct. Mater. 2014, 24, 5774– 5774A, DOI: 10.1002/adfm.201470245[Crossref], [CAS], Google Scholar319https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1yht7zJ&md5=679e980a47d54b768ae1a7b19b957f5fPhotodynamic Therapy: Highly Biocompatible Carbon Nanodots for Simultaneous Bioimaging and Targeted Photodynamic Therapy In Vitro and In Vivo (Adv. Funct. Mater. 37/2014)Choi, Yuri; Kim, Seongchan; Choi, Myung-Ho; Ryoo, Soo-Ryoon; Park, Jongnam; Min, Dal-Hee; Kim, Byeong-SuAdvanced Functional Materials (2014), 24 (37), 5774CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)There is no expanded citation for this reference.320Koo, H.; Lee, H.; Lee, S.; Min, K. H.; Kim, M. S.; Lee, D. S.; Choi, Y.; Kwon, I. C.; Kim, K.; Jeong, S. Y. In Vivo Tumor Diagnosis and Photodynamic Therapy via Tumoral PH-Responsive Polymeric Micelles. Chem. Commun. 2010, 46, 5668– 5670, DOI: 10.1039/c0cc01413c[Crossref], [PubMed], [CAS], Google Scholar320https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpsFelu7g%253D&md5=bad3e169825d5ebc92f7b399529296a3In vivo tumor diagnosis and photodynamic therapy via tumoral pH-responsive polymeric micellesKoo, Heebeom; Lee, Hyejung; Lee, Sojin; Min, Kyung Hyun; Kim, Min Sang; Lee, Doo Sung; Choi, Yongseok; Kwon, Ick Chan; Kim, Kwangmeyung; Jeong, Seo YoungChemical Communications (Cambridge, United Kingdom) (2010), 46 (31), 5668-5670CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)We report protoporphyrin IX (PpIX) encapsulated pH-responsive micelles for cancer treatment. This system showed pH-responsive micellization/demicellization transition at tumoral acidic pH and enabled in vivo tumor diagnosis and therapy simultaneously.321Lovell, J. F.; Jin, C. S.; Huynh, E.; MacDonald, T. D.; Cao, W.; Zheng, G. Enzymatic Regioselection for the Synthesis and Biodegradation of Porphysome Nanovesicles. Angew. Chem., Int. 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This enzymic screening approach and the two enzymes identified here may be useful for generating other types of isomerically pure phospholipid conjugates. Regioisomeric phospholipid conjugates can generate nanoparticles that are phys. similar, but vary greatly in how the nanoparticles biodegrade in vivo. Further research is warranted in studying the nature of enzymic biodegrdn. of nanoparticles in vivo.322Yi, X. M.; Wang, F. L.; Qin, W. J.; Yang, X. J.; Yuan, J. L. Near-Infrared Fluorescent Probes in Cancer Imaging and Therapy: An Emerging Field. Int. J. Nanomed. 2014, 9, 1347– 1365, DOI: 10.2147/IJN.S60206[Crossref], [PubMed], [CAS], Google Scholar322https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2crmvFCrsw%253D%253D&md5=de91fbc9335621319c7f65aa1a0f1787Near-infrared fluorescent probes in cancer imaging and therapy: an emerging fieldYi Xiaomin; Wang Fuli; Qin Weijun; Yang Xiaojian; Yuan JianlinInternational journal of nanomedicine (2014), 9 (), 1347-65 ISSN:.Near-infrared fluorescence (NIRF) imaging is an attractive modality for early cancer detection with high sensitivity and multi-detection capability. Due to convenient modification by conjugating with moieties of interests, NIRF probes are ideal candidates for cancer targeted imaging. Additionally, the combinatory application of NIRF imaging and other imaging modalities that can delineate anatomical structures extends fluorometric determination of biomedical information. Moreover, nanoparticles loaded with NIRF dyes and anticancer agents contribute to the synergistic management of cancer, which integrates the advantage of imaging and therapeutic functions to achieve the ultimate goal of simultaneous diagnosis and treatment. Appropriate probe design with targeting moieties can retain the original properties of NIRF and pharmacokinetics. In recent years, great efforts have been made to develop new NIRF probes with better photostability and strong fluorescence emission, leading to the discovery of numerous novel NIRF probes with fine photophysical properties. Some of these probes exhibit tumoricidal activities upon light radiation, which holds great promise in photothermal therapy, photodynamic therapy, and photoimmunotherapy. This review aims to provide a timely and concise update on emerging NIRF dyes and multifunctional agents. Their potential uses as agents for cancer specific imaging, lymph node mapping, and therapeutics are included. Recent advances of NIRF dyes in clinical use are also summarized.323Hu, J. J.; Liu, L. H.; Li, Z. Y.; Zhuo, R. X.; Zhang, X. Z. MMP-Responsive Theranostic Nanoplatform Based on Mesoporous Silica Nanoparticles for Tumor Imaging and Targeted Drug Delivery. J. Mater. Chem. B 2016, 4, 1932– 1940, DOI: 10.1039/C5TB02490K[Crossref], [PubMed], [CAS], Google Scholar323https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XisFWnuro%253D&md5=ff211b6f856f92c0d4f4d14694b20b31MMP-responsive theranostic nanoplatform based on mesoporous silica nanoparticles for tumor imaging and targeted drug deliveryHu, Jing-Jing; Liu, Li-Han; Li, Ze-Yong; Zhuo, Ren-Xi; Zhang, Xian-ZhengJournal of Materials Chemistry B: Materials for Biology and Medicine (2016), 4 (11), 1932-1940CODEN: JMCBDV; ISSN:2050-7518. (Royal Society of Chemistry)In this paper, we report on an intelligent mesoporous silica-based multifunctional theranostic nanoplatform (designated as MMTNP) for tumor imaging as well as controlled drug release. This theranostic nanoplatform consists of MCM-41 typical mesoporous silica nanoparticles (MSNs) as a hydrophobic drug carrier, matrix metalloprotease-2 (MMP-2) activated fluorescence imaging peptides on the surface of MSNs served as diagnostic probes as well as enzyme-responsive nanovalves blocking the pores, and cRGD peptides further functionalized on the surface of MSNs for tumor targeting. In the absence of MMP-2 conditions, the proximity between the fluorescent dye 5(6)-carboxytetramethylrhodamine hydrochloride (TAMRA) and the quencher 4,4-dimethylamino-azobenzene-4'-carboxylic acid (Dabcyl) on the surface of MSNs resulted in no fluorescence. When the drug loaded nanoplatform arrived at tumor tissue with overexpressed MMP-2, the fluorescence of TAMRA became recovered efficiently due to the hydrolysis of the MMP-2 sensitive peptide substrate, realizing tumor imaging and triggering drug release. In addn., the further introduced cRGD peptide significantly enhanced the targeting efficiency through receptor-mediated endocytosis in tumor cells.324Kim, J.; Tung, C. H.; Choi, Y. Smart Dual-Functional Warhead for Folate Receptor-Specific Activatable Imaging and Photodynamic Therapy. Chem. Commun. 2014, 50, 10600– 10603, DOI: 10.1039/C4CC04166F[Crossref], [PubMed], [CAS], Google Scholar324https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1aiurrE&md5=28ffa77e9f59b3e27676c30fa53eff11Smart dual-functional warhead for folate receptor-specific activatable imaging and photodynamic therapyKim, Jisu; Tung, Ching-Hsuan; Choi, YongdooChemical Communications (Cambridge, United Kingdom) (2014), 50 (73), 10600-10603CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A smart dual-targeted theranostic agent becomes highly fluorescent and phototoxic only when its linker is cleaved by tumor-assocd. lysosomal enzyme cathepsin B after internalization into folate receptor-pos. cancer cells.325Haedicke, K.; Kozlova, D.; Gräfe, S.; Teichgräber, U.; Epple, M.; Hilger, I. Multifunctional Calcium Phosphate Nanoparticles for Combining Near-Infrared Fluorescence Imaging and Photodynamic Therapy. Acta Biomater. 2015, 14, 197– 207, DOI: 10.1016/j.actbio.2014.12.009[Crossref], [PubMed], [CAS], Google Scholar325https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVCls7k%253D&md5=5e6b7752c7e07f74ec8b48f00660467eMultifunctional calcium phosphate nanoparticles for combining near-infrared fluorescence imaging and photodynamic therapyHaedicke, Katja; Kozlova, Diana; Graefe, Susanna; Teichgraeber, Ulf; Epple, Matthias; Hilger, IngridActa Biomaterialia (2015), 14 (), 197-207CODEN: ABCICB; ISSN:1742-7061. (Elsevier Ltd.)Photodynamic therapy (PDT) of tumors causes skin photosensitivity as a result of unspecific accumulation behavior of the photosensitizers. PDT of tumors was improved by calcium phosphate nanoparticles conjugated with (i) Temoporfin as a photosensitizer, (ii) the RGDfK peptide for favored tumor targeting and (iii) the fluorescent dye mol. DY682-NHS for enabling near-IR fluorescence (NIRF) optical imaging in vivo. The nanoparticles were characterized with regard to size, spectroscopic properties and uptake into CAL-27 cells. The nanoparticles had a hydrodynamic diam. of approx. 200 nm and a zeta potential of around +22 mV. Their biodistribution at 24 h after injection was investigated via NIRF optical imaging. After treating tumor-bearing CAL-27 mice with nanoparticle-PDT, the therapeutic efficacy was assessed by a fluorescent DY-734-annexin V probe at 2 days and 2 wk after treatment to detect apoptosis. Addnl., the contrast agent IRDye 800CW RGD was used to assess tumor vascularization (up to 4 wk after PDT). After nanoparticle-PDT in mice, apoptosis in the tumor was detected after 2 days. Decreases in tumor vascularization and tumor vol. were detected in the next few days. Calcium phosphate nanoparticles can be used as multifunctional tools for NIRF optical imaging, PDT and tumor targeting as they exhibited a high therapeutic efficacy, being capable of inducing apoptosis and destroying tumor vascularization.326Schneider, R.; Schmitt, F.; Frochot, C.; Fort, Y.; Lourette, N.; Guillemin, F.; Müller, J. F.; Barberi-Heyob, M. Design, Synthesis, and Biological Evaluation of Folic Acid Targeted Tetraphenylporphyrin as Novel Photosensitizers for Selective Photodynamic Therapy. Bioorg. Med. Chem. 2005, 13, 2799– 2808, DOI: 10.1016/j.bmc.2005.02.025[Crossref], [PubMed], [CAS], Google Scholar326https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXisVCgsLg%253D&md5=ca3fa28aeb2547a601c38ab8da4c7366Design, synthesis, and biological evaluation of folic acid targeted tetraphenylporphyrin as novel photosensitizers for selective photodynamic therapySchneider, Raphael; Schmitt, Frederic; Frochot, Celine; Fort, Yves; Lourette, Natacha; Guillemin, Francois; Mueller, Jean-Francois; Barberi-Heyob, MurielBioorganic & Medicinal Chemistry (2005), 13 (8), 2799-2808CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)Photodynamic therapy (PDT) is a cancer treatment involving systemic administration of a tumor-localizing photosensitizer; this, when activated by the appropriate light wavelength, interacts with mol. oxygen to form a toxic, short-lived species known as singlet oxygen, which is thought to mediate cellular death. Targeted PDT offers the opportunity of enhancing photodynamic efficiency by directly targeting diseased cells and tissues. Two new conjugates of three components, folic acid/hexane-1,6-diamine/4-carboxyphenylporphyrine 1 and folic acid/2,2'-(ethylenedioxy)-bis-ethylamine/4-carboxyphenylporphyrine 2 were synthesized. The conjugates were characterized by 1H NMR, MALDI, UV-visible spectroscopy, and fluorescence quantum yield. The targeted delivery of these photoactive compds. to KB nasopharyngeal cell line, which is one of the numerous tumor cell types that overexpress folate receptors was studied. It was found that after 24 h incubation, conjugates 1 and 2 cellular uptake was on av. 7-fold higher than tetraphenylporphyrin (TPP) used as ref. and that 1 and 2 cellular uptake kinetics increased steadily over the 24 h period, suggesting an active transport via receptor-mediated endocytosis. In corresponding results, conjugates 1 and 2 accumulation displayed a redn. of 70% in the presence of a competitive concn. of folic acid. Survival measurements demonstrated that KB cells were significantly more sensitive to conjugated porphyrins-mediated PDT. Under the same exptl. conditions and the same photosensitizer concn., TPP displayed no photocytotoxicity while conjugates 1 and 2 showed photodynamic activity with light dose values yielding 50% growth inhibition of 22.6 and 6.7 J/cm2, resp.327Wang, F.; Chen, X.; Zhao, Z.; Tang, S.; Huang, X.; Lin, C.; Cai, C.; Zheng, N. Synthesis of Magnetic, Fluorescent and Mesoporous Core-Shell-Structured Nanoparticles for Imaging, Targeting and Photodynamic Therapy. J. Mater. Chem. 2011, 21, 11244– 11252, DOI: 10.1039/c1jm10329f[Crossref], [CAS], Google Scholar327https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptVyns7c%253D&md5=e7b815671445fd55612c38bb43422e22Synthesis of magnetic, fluorescent and mesoporous core-shell-structured nanoparticles for imaging, targeting and photodynamic therapyWang, Fang; Chen, Xiao-Lan; Zhao, Zeng-Xia; Tang, Shao-Heng; Huang, Xiao-Qing; Lin, Cheng-Hong; Cai, Cong-bo; Zheng, Nan-FengJournal of Materials Chemistry (2011), 21 (30), 11244-11252CODEN: JMACEP; ISSN:0959-9428. (Royal Society of Chemistry)A synthetic method to prep. novel multifunctional core-shell-structured mesoporous silica nanoparticles for simultaneous magnetic resonance (MR) and fluorescence imaging, cell targeting and photosensitization treatment has been developed. Superparamagnetic magnetite nanoparticles and fluorescent dyes are co-encapsulated inside nonporous silica nanoparticles as the core to provide dual-imaging capabilities (MR and optical). The photosensitizer mols., tetra-substituted carboxyl aluminum phthalocyanine (AlC4Pc), are covalently linked to the mesoporous silica shell and exhibit excellent photo-oxidn. efficiency. The surface modification of the core-shell silica nanoparticles with folic acid enhances the delivery of photosensitizers to the targeting cancer cells that overexpress the folate receptor, and thereby decreases their toxicity to the surrounding normal tissues. These unique advantages make the prepd. multifunctional core-shell silica nanoparticles promising for cancer diagnosis and therapy.328Kenanova, V.; Wu, A. M. Tailoring Antibodies for Radionuclide Delivery. Expert Opin. Drug Delivery 2006, 3, 53– 70, DOI: 10.1517/17425247.3.1.53[Crossref], [PubMed], [CAS], Google Scholar328https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtlCms7zI&md5=72b11b620ba7250589ef7fa8d0b1d870Tailoring antibodies for radionuclide deliveryKenanova, Vania; Wu, Anna M.Expert Opinion on Drug Delivery (2006), 3 (1), 53-70CODEN: EODDAW; ISSN:1742-5247. (Ashley Publications Ltd.)A review. Therapeutic antibodies are well established as an important class of drugs in modern medicine. The exquisite specificity and affinity for a specific target offered by antibodies has also encouraged their development as delivery vehicles for agents such as radionuclides to target tissues, for radioimmunoimaging and radioimmunotherapy. Specifically, in nuclear medicine, radionuclide-conjugated antibody mols. make it possible to image diseased loci with greater sensitivity than other imaging modalities such as magnetic resonance imaging. Furthermore, two radionuclide-conjugated antibodies have recently been approved for the therapy of non-Hodgkin's lymphoma. However, optimal implementation of antibodies has been limited by the extended circulation persistence that is characteristic of native antibodies, which is responsible for increased background activity in radioimmunoimaging applications and dose-related normal organ toxicities in radioimmunotherapy. In this article the current status of radiolabeled intact antibodies is reviewed, focusing on strategies to improve their pharmacokinetic properties to suit a desired application. Examples from the literature that represent different approaches to accomplishing this task in terms of their successes as well as limitations, and perspectives for the future are discussed.329Vieira, P.; Rajewsky, K. The Half-Lives of Serum Immunoglobulins in Adult Mice. Eur. J. Immunol. 1988, 18, 313– 316, DOI: 10.1002/eji.1830180221[Crossref], [PubMed], [CAS], Google Scholar329https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXhvVCrs7Y%253D&md5=2c644134b8964794b3391b7c796f8537The half-lives of serum immunoglobulins in adult miceVieira, Paulo; Rajewsky, KlausEuropean Journal of Immunology (1988), 18 (2), 313-16CODEN: EJIMAF; ISSN:0014-2980.The half-lives were detd. of several sets of murine monoclonal antibodies spanning all Ig isotypes in the serum. The antibodies in each set possess the same V region. With this approach, the differences in half-life obsd. between the different isotypes are independent of the V region carried by the monoclonal antibodies and therefore must relate to each other in the same way as the half-lives of each class of serum Igs. The half-life of a monoclonal antibody of the γ2a isotype is identical to the av. half-life of serum IgG2a as previously detd. (6-8 days). Therefore, the half-lives detd. with monoclonal antibodies possessing the same V region represent the half-life of the serum Igs. In this way, the half-life of IgM was calcd. to be 2 days, IgG3 and IgG1 was 6-8 days, and IgG2b was 4-6 days. IgE has a half-life of 12 h. A polymeric form of IgA was eliminated from the serum with a half-life of 17-22 h.330Decristoforo, C.; Pickett, R. D.; Verbruggen, A. Feasibility and Availability of 68Ga-Labelled Peptides. Eur. J. Nucl. Med. Mol. Imaging 2012, 39, 31– 40, DOI: 10.1007/s00259-011-1988-5[Crossref], [PubMed], [CAS], Google Scholar330https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xkt1CktLg%253D&md5=2b0b68682a998710c9efb7c87515e41bFeasibility and availability of 68Ga-labelled peptidesDecristoforo, Clemens; Pickett, Roger D.; Verbruggen, AlfonsEuropean Journal of Nuclear Medicine and Molecular Imaging (2012), 39 (Suppl.1), 31-40CODEN: EJNMA6; ISSN:1619-7070. (Springer)A review. 68Ga has attracted tremendous interest as a radionuclide for PET based on its suitable half-life of 68 min, high positron emission yield and ready availability from 68Ge/68Ga generators, making it independent of cyclotron prodn. 68Ga-labeled DOTA-conjugated somatostatin analogs, including DOTA-TOC, DOTA-TATE and DOTA-NOC, have driven the development of technologies to provide such radiopharmaceuticals for clin. applications mainly in the diagnosis of somatostatin receptor-expressing tumors. We summarize the issues detg. the feasibility and availability of 68Ga-labeled peptides, including generator technol., 68Ga generator eluate postprocessing methods, radiolabelling, automation and peptide developments, and also quality assurance and regulatory aspects. 68Ge/68Ga generators based on SnO2, TiO2 or org. matrixes are today routinely supplied to nuclear medicine departments, and a variety of automated systems for postprocessing and radiolabelling have been developed. New developments include improved chelators for 68Ga that could open new ways to utilize this technol. Challenges and limitations in the on-site prepn. and use of 68Ga-labeled peptides outside the marketing authorization track are also discussed.331Liang, B.; Shao, W.; Zhu, C.; Wen, G.; Yue, X.; Wang, R.; Quan, J.; Du, J.; Bu, X. Mitochondria-Targeted Approach: Remarkably Enhanced Cellular Bioactivities of TPP2a as Selective Inhibitor and Probe toward TrxR. ACS Chem. Biol. 2016, 11, 425– 434, DOI: 10.1021/acschembio.5b00708[ACS Full Text], [CAS], Google Scholar331https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVCks7c%253D&md5=e4daaa0034ea25288d022bd8ee16996fMitochondria-Targeted Approach: Remarkably Enhanced Cellular Bioactivities of TPP2a as Selective Inhibitor and Probe toward TrxRLiang, Baoxia; Shao, Weiyan; Zhu, Cuige; Wen, Gesi; Yue, Xin; Wang, Ruimin; Quan, Junmin; Du, Jun; Bu, XianzhangACS Chemical Biology (2016), 11 (2), 425-434CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)A mitochondria-targeted approach was developed to increase the cellular bioactivities of thioredoxin reductase (TrxR) inhibitors. By being conjugated with a triphenylphosphine (TPP) motif to a previously found TrxR inhibitor I (R = H), the resulted compd. TPP2a [I; R = (CH2)10P+Ph3 Br-] can target subcellular mitochondria and efficiently inhibit cellular TrxR, leading to remarkably increased cellular ROS level and mitochondrial apoptosis of HeLa cancer cells. The cellular bioactivities of TPP2a, including its cytotoxicity against a panel of cancer cell lines, dramatically elevated compared with its parental compd. I (R = H). The selectively and covalently interaction of TPP2a with subcellular mitochondrial TrxR was validated by fluorescent microscopy. Moreover, a nonspecific signal quenching coupled strategy was proposed based on the environmentally sensitive fluorescence of TPP2a, which makes it possible to label TrxR by removing the nonspecific backgrounds caused by TPP2a under complex biosettings such as cellular lysates and living cells, implicating a potential of TPP2a for TrxR-specific labeling.332Isabel, M.; Prata, M. Gallium-68: A New Trend in PET Radiopharmacy. Curr. Radiopharm. 2012, 5, 142– 149, DOI: 10.2174/1874471011205020142333Roesch, F. Maturation of a Key Resource – The Germanium-68/Gallium-68 Generator: Development and New Insights. Curr. Radiopharm. 2012, 5, 202– 211, DOI: 10.2174/1874471011205030202[Crossref], [PubMed], [CAS], Google Scholar333https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtF2jt77N&md5=55b95e6a5982d3243c6225b18ec751f4Maturation of a key resource - the germanium-68/gallium-68 generator: development and new insightsRoesch, F.Current Radiopharmaceuticals (2012), 5 (3), 202-211CODEN: CRUAC7; ISSN:1874-4710. (Bentham Science Publishers Ltd.)A review. 68Ge/68Ga radionuclide generators have been investigated for almost fifty years, since the cyclotronindependent availability of positron emitting 68Ga via the 68Ge/68Ga system had always attracted researches working in basic nuclear chem. as well as radiopharmaceutical chem. However, it took decades and generations of research (and researchers) to finally reach a level of 68Ge/68Ga radionuclide generator designs adequate to the modern requirements of radiometal labeling chem. Nevertheless, most of the existing com. generator systems address aspects of 68Ge breakthrough and safe synthesis of 68Ga radiopharmaceuticals by adopting eluate post-processing technologies. Among the strategies to purify 68Ga eluates, the cation exchange based version is relevant in terms of purifn. efficiency. In addn., it offers more options towards further developments of 68Ga radiopharmaceuticals. Today, one may expect that the 68Ge/68Ga radionuclide generator systems could contribute to the clin. impact of nuclear medicine diagnoses for PET similar to the established 99Mo/99mTc generator system for SPECT. The exciting perspective for the 68Ge/68Ga radionuclide generator system, in turn, asks for systematic chem., radiochem., technol. and radiopharmaceutical efforts, to guarantee reliable, highly-efficient and medically approved 68Ge/68Ga generator systems.334Gaedicke, S.; Braun, F.; Prasad, S.; Machein, M.; Firat, E.; Hettich, M.; Gudihal, R.; Zhu, X.; Klingner, K.; Schüler, J.; Herold-Mende, C. C.; Grosu, A. L.; Behe, M.; Weber, W.; Mäcke, H.; Niedermann, G. Noninvasive Positron Emission Tomography and Fluorescence Imaging of CD133+ Tumor Stem Cells. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, E692– E701, DOI: 10.1073/pnas.1314189111[Crossref], [PubMed], [CAS], Google Scholar334https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisFyisLw%253D&md5=462b7d9036c71db86e72bddd060cc2c1Noninvasive positron emission tomography and fluorescence imaging of CD133+ tumor stem cellsGaedicke, Simone; Braun, Friederike; Prasad, Shruthi; Machein, Marcia; Firat, Elke; Hettich, Michael; Gudihal, Ravindra; Zhu, Xuekai; Klingner, Kerstin; Schueler, Julia; Herold-Mende, Christel C.; Grosu, Anca-Ligia; Behe, Martin; Weber, Wolfgang; Maecke, Helmut; Niedermann, GabrieleProceedings of the National Academy of Sciences of the United States of America (2014), 111 (6), E692-E701CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)A technol. that visualizes tumor stem cells with clin. relevant tracers could have a broad impact on cancer diagnosis and treatment. The AC133 epitope of CD133 currently is one of the best-characterized tumor stem cell markers for many intra- and extracranial tumor entities. Here we demonstrate the successful noninvasive detection of AC133+ tumor stem cells by PET and near-IR fluorescence mol. tomog. in s.c. and orthotopic glioma xenografts using antibody-based tracers. Particularly, microPET with 64Cu-NOTA-AC133 mAb yielded high-quality images with outstanding tumor-to-background contrast, clearly delineating s.c. tumor stem cell-derived xenografts from surrounding tissues. Intracerebral tumors as small as 2-3 mm also were clearly discernible, and the microPET images reflected the invasive growth pattern of orthotopic cancer stem cell-derived tumors with low d. of AC133+ cells. These data provide a basis for further preclin. and clin. use of the developed tracers for high-sensitivity and high-resoln. monitoring of AC133+ tumor stem cells.335Cho, Y. W.; Park, S. A.; Han, T. H.; Son, D. H.; Park, J. S.; Oh, S. J.; Moon, D. H.; Cho, K. J.; Ahn, C. H.; Byun, Y.; Kim, I. S.; Kwon, I. C.; Kim, S. Y. Vivo Tumor Targeting and Radionuclide Imaging with Self-Assembled Nanoparticles: Mechanisms, Key Factors, and Their Implications. Biomaterials 2007, 28, 1236– 1247, DOI: 10.1016/j.biomaterials.2006.10.002[Crossref], [PubMed], [CAS], Google Scholar335https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28npvFyrtw%253D%253D&md5=9ad41e501a48abb893e83056eca0ba5eIn vivo tumor targeting and radionuclide imaging with self-assembled nanoparticles: mechanisms, key factors, and their implicationsCho Yong Woo; Park Soo Ah; Han Tae Hee; Son Dai Hyun; Park Ji Sun; Oh Seung Jun; Moon Dae Hyuk; Cho Kyung-Ja; Ahn Cheol-Hee; Byun Youngro; Kim In-San; Kwon Ick Chan; Kim Sang YoonBiomaterials (2007), 28 (6), 1236-47 ISSN:0142-9612.The development of more selective delivery systems for cancer diagnosis and chemotherapy is one of the most important goals of current anticancer research. The purpose of this study is to evaluate various self-assembled nanoparticles as candidates to shuttle radionuclide and/or drugs into tumors and to investigate the mechanisms underlying the tumor targeting with self-assembled nanoparticles. By combining different hydrophobic moieties and hydrophilic polymer backbones, various self-assembled nanoparticles were prepared, and their in vivo distributions in tumor-bearing mice were studied by radionuclide imaging. One type of nanoparticles (fluorescein isothiocyanate-conjugated glycol chitosan (FGC) nanoparticles) exhibited highly selective tumoral localization. Scintigraphic images obtained 1 day after the intravenous injection of FGC nanoparticles clearly delineated the tumor against adjacent tissues. The mechanisms underlying the tumor targeting with self-assembled nanoparticles were investigated in terms of the physicochemical properties of nanoparticles and tumor microenvironments. FGC nanoparticles were preferentially localized in perivascular regions, implying their extravasation to tumors through the hyperpermeable tumor vasculature. The magnitude and pattern of tumoral distribution of self-assembled nanoparticles were influenced by several key factors--(i) in vivo colloidal stability: nanoparticles should maintain their intact nanostructures in vivo for a long period of time, (ii) particle size, (iii) intracellular uptake of nanoparticle: fast cellular uptake greatly facilitates the tumor targeting, (iv) tumor angiogenesis: pathological angiogenesis permits access of nanoparticles to tumors. We believe that this work can provide insight for the engineering of nanoparticles and be extended to cancer therapy and diagnosis, so as to deliver multiple therapeutic agents and imaging probes at high local concentrations.336Mitra, A.; Nan, A.; Line, B.; Ghandehari, H. Nanocarriers for Nuclear Imaging and Radiotherapy of Cancer. Curr. Pharm. Des. 2006, 12, 4729– 4749, DOI: 10.2174/138161206779026317[Crossref], [PubMed], [CAS], Google Scholar336https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsFCntw%253D%253D&md5=f09fa5d43f3bb98949d5fe6967a1fe12Nanocarriers for nuclear imaging and radiotherapy of cancerMitra, Amitava; Nan, Anjan; Line, Bruce R.; Ghandehari, HamidrezaCurrent Pharmaceutical Design (2006), 12 (36), 4729-4749CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)A review. Several nanoscale carriers (nanoparticles, liposomes, water-sol. polymers, micelles and dendrimers) have been developed for targeted delivery of cancer diagnostic and therapeutic agents. These carriers can selectively target cancer sites and carry large payloads, thereby improving cancer detection and therapy effectiveness. Further, the combination of newer nuclear imaging techniques providing high sensitivity and spatial resoln. such as dual modality imaging with positron emission tomog./computed tomog. and use of nanoscale devices to carry diagnostic and therapeutic radionuclides with high target specificity can enable more accurate detection, staging and therapy planning of cancer. The successful clin. applications of radiolabeled monoclonal antibodies for cancer detection and therapy bode well for the future of nanoscale carrier systems in clin. oncol. Several radiolabeled multifunctional nanocarriers have been effective in detecting and treating cancer in animal models. Nonetheless, further preclin., clin. and long-term toxicity studies will be required to translate this technol. to the care of patients with cancer. The objective of this review is to present a brief but comprehensive overview of the various nuclear imaging techniques and the use of nanocarriers to deliver radionuclides for the diagnosis and therapy of cancer.337Yamamoto, F.; Yamahara, R.; Makino, A.; Kurihara, K.; Tsukada, H.; Hara, E.; Hara, I.; Kizaka-Kondoh, S.; Ohkubo, Y.; Ozeki, E.; Kimura, S. Radiosynthesis and Initial Evaluation of 18F Labeled Nanocarrier Composed of Poly(L-Lactic Acid)-Block-Poly(Sarcosine) Amphiphilic Polydepsipeptide. Nucl. Med. Biol. 2013, 40, 387– 394, DOI: 10.1016/j.nucmedbio.2012.12.008[Crossref], [PubMed], [CAS], Google Scholar337https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlahtbo%253D&md5=4b4daf1469bf6c476c61fee355f009f2Radiosynthesis and initial evaluation of 18F labeled nanocarrier composed of poly(L-lactic acid)-block-poly(sarcosine) amphiphilic polydepsipeptideYamamoto, Fumihiko; Yamahara, Ryo; Makino, Akira; Kurihara, Kensuke; Tsukada, Hideo; Hara, Eri; Hara, Isao; Kizaka-Kondoh, Shinae; Ohkubo, Yasuhito; Ozeki, Eiichi; Kimura, ShunsakuNuclear Medicine and Biology (2013), 40 (3), 387-394CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)With the aim of developing radiotracers for in vivo positron emission tomog. (PET) imaging of solid tumors based on the enhanced permeability and retention effect of nanocarriers, we have developed a polymer micelle named "Lactosome", which is composed of the amphiphilic polydepsipeptide, poly(L-lactic acid)-block-poly(sarcosine). This paper describes and evaluates the initial evaluation of the 18F-labeled Lactosome as a novel contrast agent for the tumor PET imaging technique carried out. 18F-labeled Lactosomes were prepd. by a film hydration method under sonication in water at 50 °C from a mixt. of 4-[18F]fluoro-benzoyl poly-L-lactic acid (18F-BzPLLA30) and the amphiphilic polydepsipeptide. For biodistribution studies, BALB/cA Jcl-nu/nu mice bearing HeLa cells in the femur region were used. We took both PET and near-IR fluorescence (NIRF) images of tumor bearing mice after co-injection of 18F-labeled Lactosome and NIRF-labeled Lactosome. 18F-labeled Lactosomes were prepd. at good yields (222-420 MBq) and more than 99% of 18F-BzPLLA30 was incorporated into 18F-labeled Lactosome. The radioactivity of 18F-labeled Lactosome was found to be stable and maintained at high level for up to 6 h after injection into the blood stream. Tumor uptake increased gradually after the injection. The uptake ratio of tumor/muscle was 2.7 at 6 h from the time of injection. Tumor PET imaging with 18F-labeled Lactosome was as capable as tumor NIRF imaging with NIRF-labeled Lactosome. Tumor PET imaging using Lactosome as a nanocarrier may be therefore a potential candidate for a facile and general solid tumor imaging technique.338Jerabek, P. A.; Patrick, T. B.; Kilbourn, M. R.; Dischino, D. D.; Welch, M. J. Synthesis and Biodistribution of 18F-Labeled Fluoronitroimidazoles: Potential in Vivo Markers of Hypoxic Tissue. Int. J. Radiat. Appl. Instrumentation. 1986, 37, 599– 605, DOI: 10.1016/0883-2889(86)90079-1[Crossref], [CAS], Google Scholar338https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2s%252Fjt12lsw%253D%253D&md5=5b8bf557eec0bf94f118772f48940015Synthesis and biodistribution of 18F-labeled fluoronitroimidazoles: potential in vivo markers of hypoxic tissueJerabek P A; Patrick T B; Kilbourn M R; Dischino D D; Welch M JInternational journal of radiation applications and instrumentation. Part A, Applied radiation and isotopes (1986), 37 (7), 599-605 ISSN:0883-2889.Three 18F labeled fluoronitroimidazoles have been prepared as potential in vivo markers of hypoxic cells in tumors, and ischemic areas of the heart and brain. 1-(2-Nitroimidazolyl)-3-[18F]fluoro-2-hydroxypropanol (18F]fluoro-normethoxymisonidazole) 4, 1-(2-[18F]fluoroethyl)-2-nitroimidazole 7, and 1-(2-[18F]-fluoroethyl)-2-methyl-5-nitroimidazole ([18F]fluoro-norhydroxymetronidazole) 10 were prepared in average radiochemical yields of less than 1%, 23% and 15-43% (8% at the no carrier-added level) respectively at end-of-synthesis. The in vivo biodistribution in rats was determined for each of the 18F labeled fluoronitroimidazoles. At 1 and 3 h after administration, the tissue distribution of each of the 18F labeled nitroimidzaoles was quite uniform and consistent with that of nitroimidazoles previously studied. These results suggest the need for a suitable animal model to evaluate their potential as in vivo markers of hypoxic tissue in the brain.339Grierson, J. R.; Link, J. M.; Mathis, C. A.; Rasey, J. S.; Krohn, K. A. A Radiosynthesis of Fluorine-18 Fluoromisonidazole. J. Labelled Compd. Radiopharm. 1989, 30, 343– 350, DOI: 10.1002/jlcr.2580260104340Lopci, E.; Grassi, I.; Chiti, A.; Nanni, C.; Cicoria, G.; Toschi, L.; Fonti, C.; Lodi, F.; Mattioli, S.; Fanti, S. Pet Radiopharmaceuticals for Imaging of Tumor Hypoxia: A Review of the Evidence. Am. J. Nucl. Med. Mol. Imaging 2014, 4, 365– 384[PubMed], [CAS], Google Scholar340https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1egtLrI&md5=c7b7de8f5e17092cb361bb4b51173474PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidenceLopci, Egesta; Grassi, Ilaria; Chiti, Arturo; Nanni, Cristina; Cicoria, Gianfranco; Toschi, Luca; Fonti, Cristina; Lodi, Filippo; Mattioli, Sandro; Fanti, StefanoAmerican Journal of Nuclear Medicine and Molecular Imaging (2014), 4 (4), 365-384, 20 pp.CODEN: AJNMAU; ISSN:2160-8407. (e-Century Publishing Corp.)A review. Hypoxia is a pathol. condition arising in living tissues when oxygen supply does not adequately cover the cellular metabolic demand. Detection of this phenomenon in tumors is of the utmost clin. relevance because tumor aggressiveness, metastatic spread, failure to achieve tumor control, increased rate of recurrence, and ultimate poor outcome are all assocd. with hypoxia. Consequently, in recent decades there has been increasing interest in developing methods for measurement of oxygen levels in tumors. Among the image-based modalities for hypoxia assessment, positron emission tomog. (PET) is one of the most extensively investigated based on the various advantages it offers, i.e., broad range of radiopharmaceuticals, good intrinsic resoln., three-dimensional tumor representation, possibility of semiquantification/quantification of the amt. of hypoxic tumor burden, overall patient friendliness, and ease of repetition. Compared with the other non-invasive techniques, the biggest advantage of PET imaging is that it offers the highest specificity for detection of hypoxic tissue. Starting with the 2-nitroimidazole family of compds. in the early 1980s, a great no. of PET tracers have been developed for the identification of hypoxia in living tissue and solid tumors. This paper provides an overview of the principal PET tracers applied in cancer imaging of hypoxia and discusses in detail their advantages and pitfalls.341Bourgeois, M.; Rajerison, H.; Guerard, F.; Mougin-Degraef, M.; Barbet, J.; Michel, N.; Cherel, M.; Faivre-Chauvet, A. Contribution of [64Cu]-ATSM PET in Molecular Imaging of Tumour Hypoxia Compared to Classical [18F] - MISO - A Selected Review. Nucl. Med. Rev. 2011, 14, 90– 95, DOI: 10.5603/NMR.2011.00022[Crossref], [PubMed], [CAS], Google Scholar341https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC387itVSmuw%253D%253D&md5=411baf3264eedd5abc229b864a92f424Contribution of [64Cu]-ATSM PET in molecular imaging of tumour hypoxia compared to classical [18F]-MISO--a selected reviewBourgeois Mickael; Rajerison Holisoa; Guerard Francois; Mougin-Degraef Marie; Barbet Jacques; Michel Nathalie; Cherel Michel; Faivre-Chauvet AlainNuclear medicine review. Central & Eastern Europe (2011), 14 (2), 90-5 ISSN:.During the carcinogenesis process, tumour cells often have a more rapid proliferation potential than cells that participate in blood capillary formation by neoangiogenesis. As a consequence of the poorly organized vasculature of various solid tumours, a limited oxygen delivery is observed. This hypoxic mechanism frequently occurs in solid cancers and can lead to therapeutic resistance. The present selected literature review is focused on the comparison of two positron emitting radiopharmaceuticals agents, which are currently leaders in tumour hypoxia imaging by PET. {18F}-fluoromisonidazole (=FMISO) is most commonly used as an investigational PET agent with an investigational new drug exemption from the FDA, while {64Cu}-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) has been presented as an alternative radiopharmaceutical not yet readily available. The comparison of these two radiopharmaceutical agents is particularly focused on isotope properties, radiopharmaceutical labelling process, pharmacological mechanisms, dosimetry data in patients, and clinical results in terms of image contrast. PET imaging has demonstrated a good efficacy in tumour hypoxia imaging with both FMISO and Cu-ATSM, but FMISO has presented too slow an in vivo accumulation and a weak image contrast of the hypoxia area. Despite a less favourable dosimetry, 64Cu-ATSM appears superior in terms of imaging performance, calling for industrial and clinical development of this innovative radiopharmaceutical.342Hoigebazar, L.; Jeong, J. M. Hypoxia Imaging Agents Labeled with Positron Emitters. Recent Results Cancer Res. 2013, 194, 285– 299, DOI: 10.1007/978-3-642-27994-2_15[Crossref], [PubMed], [CAS], Google Scholar342https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXltVehtLY%253D&md5=4627e341d2501557758eddba21b6cc32Hypoxia Imaging Agents Labeled with Positron EmittersHoigebazar, Lathika; Jeong, Jae MinRecent Results in Cancer Research (2013), 194 (Theranostics, Gallium-68, and Other Radionuclides), 285-299CODEN: RRCRBU; ISSN:0080-0015. (Springer GmbH)A review. Imaging hypoxia using positron emission tomog. (PET) is of great importance for therapy of cancer. [18 F]Fluoromisonidazole (FMISO) was the first PET agent for hypoxia imaging, and various radiolabeled nitroimidazole derivs. such as [18 F]fluoroerythronitroimidazole (FETNIM), [18 F]1-α- d -(2-deoxy-2-fluoroarabinofuranosyl)-2-nitroimidazole (FAZA), [18 F]2-(2-nitro-1 H -imidazol-1-yl)- N -(2,2,3,3,3-pentafluoropropyl) acetamide (EF-5), and [18 F]fluoroetanidazole (FETA) have been developed successively. To overcome the high cost of cyclotron installation, 68 Ga-labeled nitroimidazole derivs. also have been developed. Another important hypoxia imaging agent is 64 Cu-diacetyl-bis( N 4 -methylthiosemicarbazone) (64 Cu-ATSM), which can distribute in cancer tissue rapidly due to high lipophilicity. However, its application is limited due to high cost of radionuclide prodn. Although various hypoxia imaging agents have been reported and tested, hypoxia PET images still have to be improved, because of the low blood flow in hypoxic tissues and resulting low uptake of the agents.343Takasawa, M.; Moustafa, R. R.; Baron, J. C. Applications of Nitroimidazole in Vivo Hypoxia Imaging in Ischemic Stroke. Stroke 2008, 39, 1629– 1637, DOI: 10.1161/STROKEAHA.107.485938[Crossref], [PubMed], [CAS], Google Scholar343https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkvVeit7g%253D&md5=869d47fe812ae6e763103df84e0f9e9cApplications of Nitroimidazole In Vivo Hypoxia Imaging in Ischemic StrokeTakasawa, Masashi; Moustafa, Ramez Reda; Baron, Jean-ClaudeStroke (2008), 39 (5), 1629-1637CODEN: SJCCA7; ISSN:0039-2499. (Lippincott Williams & Wilkins)A review. Background and Purpose: Nitroimidazole imaging is a promising contender for noninvasive in vivo mapping of brain hypoxia after stroke. However, there is a dearth of knowledge about the behavior of these compds. in the various pathophysiol. situations encountered in ischemic stroke. In this article we report the findings from a systematic review of the literature on the use of the nitroimidazoles to map hypoxia after stroke. Summary of Review: We describe the characteristics of nitroimidazoles as imaging tracers, their pharmacol., and results of both animal and clin. studies during and after focal cerebral ischemia. Findings in brain tumors are also presented to the extent that they enlighten results in stroke. Early results from application of kinetic modeling for quant. measurement of tracer binding are briefly discussed. Conclusions: Based on this literature review, nitroimidazole hypoxia imaging agents are of considerable interest in stroke because they appear, both in animal models and in humans, to specifically detect the severely hypoxic viable tissue, but not the reperfused nor the necrotic tissue. To fully realize this potential in stroke, however, formal validation by concurrent measurement of tissue oxygen tension, together with development of novel ligands with faster distribution kinetics, faster clearance from normal tissue, and well-defined trapping mechanisms, are important goals for future investigations.344Lee, N. Y.; Mechalakos, J. G.; Nehmeh, S.; Lin, Z.; Squire, O. D.; Cai, S.; Chan, K.; Zanzonico, P. B.; Greco, C.; Ling, C. C.; Humm, J. L.; Schöder, H. Fluorine-18-Labeled Fluoromisonidazole Positron Emission and Computed Tomography-Guided Intensity-Modulated Radiotherapy for Head and Neck Cancer: A Feasibility Study. Int. Int. J. Radiat. Oncol., Biol., Phys. 2008, 70, 2– 13, DOI: 10.1016/j.ijrobp.2007.06.039[Crossref], [PubMed], [CAS], Google Scholar344https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsVentrzN&md5=6ec6605b523114de78dfe2c41cce3cccFluorine-18-Labeled Fluoromisonidazole Positron Emission and Computed Tomography-Guided Intensity-Modulated Radiotherapy for Head and Neck Cancer: A Feasibility StudyLee, Nancy Y.; Mechalakos, James G.; Nehmeh, Sadek; Lin, Zhixiong; Squire, Olivia D.; Cai, Shangde; Chan, Kelvin; Zanzonico, Pasquale B.; Greco, Carlo; Ling, Clifton C.; Humm, John L.; Schoder, HeikoInternational Journal of Radiation Oncology, Biology, Physics (2008), 70 (1), 2-13CODEN: IOBPD3; ISSN:0360-3016. (Elsevier Inc.)Purpose: Hypoxia renders tumor cells radioresistant, limiting locoregional control from radiotherapy (RT). Intensity-modulated RT (IMRT) allows for targeting of the gross tumor vol. (GTV) and can potentially deliver a greater dose to hypoxic subvolumes (GTVh) while sparing normal tissues. A Monte Carlo model has shown that boosting the GTVh increases the tumor control probability. This study examd. the feasibility of fluorine-18-labeled fluoromisonidazole positron emission tomog./computed tomog. (18F-FMISO PET/CT)-guided IMRT with the goal of maximally escalating the dose to radioresistant hypoxic zones in a cohort of head and neck cancer (HNC) patients. Methods and Materials: 18F-FMISO was administered i.v. for PET imaging. The CT simulation, fluorodeoxyglucose PET/CT, and 18F-FMISO PET/CT scans were co-registered using the same immobilization methods. The tumor boundaries were defined by clin. examn. and available imaging studies, including fluorodeoxyglucose PET/CT. Regions of elevated 18F-FMISO uptake within the fluorodeoxyglucose PET/CT GTV were targeted for an IMRT boost. Addnl. targets and/or normal structures were contoured or transferred to treatment planning to generate 18F-FMISO PET/CT-guided IMRT plans. Results: The heterogeneous distribution of 18F-FMISO within the GTV demonstrated variable levels of hypoxia within the tumor. Plans directed at performing 18F-FMISO PET/CT-guided IMRT for 10 HNC patients achieved 84 Gy to the GTVh and 70 Gy to the GTV, without exceeding the normal tissue tolerance. We also attempted to deliver 105 Gy to the GTVh for 2 patients and were successful in 1, with normal tissue sparing. Conclusion: It was feasible to dose escalate the GTVh to 84 Gy in all 10 patients and in 1 patient to 105 Gy without exceeding the normal tissue tolerance. This information has provided important data for subsequent hypoxia-guided IMRT trials with the goal of further improving locoregional control in HNC patients.345Padhani, A. R. Where Are We With Imaging Oxygenation in Human Tumours?. Cancer Imaging 2005, 5, 128– 130, DOI: 10.1102/1470-7330.2005.0103[Crossref], [PubMed], [CAS], Google Scholar345https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MnktVWrsw%253D%253D&md5=059f6113c7f0fffabb1e4f028050e481Where are we with imaging oxygenation in human tumours?Padhani Anwar RCancer imaging : the official publication of the International Cancer Imaging Society (2005), 5 (), 128-30 ISSN:.Tumour hypoxia represents a significant challenge to the curability of human tumours leading to treatment resistance and enhanced tumour regression. Tumour hypoxia can be detected by non-invasive techniques but the interrelationship between these techniques needs to be better defined. [18F]Fluoromisonidazole (18F-MISO) and Cu-labelled diacetyl-bis(N(4)-methylthiosemicarbazone (Cu-ATSM) PET, and blood oxygen level-dependent (BOLD) MRI are the lead contenders for human application based on their non-invasive nature, ease of use and robustness, measurement of hypoxia status, validity, ability to demonstrate heterogeneity and general availability; these techniques are the primary focus of this editorial.346Lapi, S. E.; Voller, T. F.; Welch, M. J. PET Imaging of Hypoxia. PET Clin 2009, 4, 39– 47, DOI: 10.1016/j.cpet.2009.05.009[Crossref], [PubMed], [CAS], Google Scholar346https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2srlvFCgtg%253D%253D&md5=74255e1aa7a6dd21fc247a3a219642a2Positron Emission Tomography Imaging of HypoxiaLapi Suzanne E; Voller Thomas F; Welch Michael JPET clinics (2009), 4 (1), 39-47 ISSN:.Hypoxia imaging has applications in functional recovery in ischemic events such as stroke and myocardial ischemia, but especially in tumors in which hypoxia can be predictive of treatment response and overall prognosis. Recently there has been development of imaging agents utilizing positron emission tomography for non-invasive imaging of hypoxia. Many of these PET agents have come to the forefront of hypoxia imaging. Halogenated PET nitroimidazole imaging agents labeled with (18)F (t(1/2) = 110 m) and (124)I (t(1/2) = 110 m) have been under investigation for the last 25 years, with radiometal agents ((64)Cu-ATSM) being developed more recently. This review focuses on these positron emission tomography imaging agents for hypoxia.347Hustinx, R.; Eck, S. L.; Alavi, A. Potential Applications of PET Imaging in Developing Novel Cancer Therapies. J. Nucl. Med. 2000, 11, 433– 441, DOI: 10.1016/S1051-0443(00)70185-0348Chen, K.; Chen, X. Positron Emission Tomography Imaging of Cancer Biology: Current Status and Future Prospects. Semin. Oncol. 2011, 38, 70– 86, DOI: 10.1053/j.seminoncol.2010.11.005[Crossref], [PubMed], [CAS], Google Scholar348https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M3jtVSlsg%253D%253D&md5=04fa5dbe375a168456211153d2ed29eePositron emission tomography imaging of cancer biology: current status and future prospectsChen Kai; Chen XiaoyuanSeminars in oncology (2011), 38 (1), 70-86 ISSN:.Positron emission tomography (PET) is one of the most rapidly growing areas of medical imaging, with many applications in the clinical management of patients with cancer. The principal goal of PET imaging is to visualize, characterize, and measure biological processes at the cellular, subcellular, and molecular levels in living subjects using noninvasive procedures. PET imaging takes advantage of the traditional diagnostic imaging techniques and introduces positron-emitting probes to determine the expression of indicative molecular targets at different stages of cancer progression. Although [(18)F]fluorodeoxyglucose ([(18)F]FDG)-PET has been widely utilized for staging and restaging of cancer, evaluation of response to treatment, differentiation of post-therapy alterations from residual or recurrent tumor, and assessment of prognosis, [(18)F]FDG is not a target-specific PET tracer. Over the last decade, numerous target-specific PET tracers have been developed and evaluated in preclinical and clinical studies. This review provides an overview of the current status and trends in the development of non-[(18)F]FDG PET probes in oncology and their application in the investigation of cancer biology.349Zhang, P.; Sadler, P. J. Redox-Active Metal Complexes for Anticancer Therapy. Eur. J. Inorg. Chem. 2017, 2017, 1541– 1548, DOI: 10.1002/ejic.201600908[Crossref], [CAS], Google Scholar349https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjsFejsrw%253D&md5=f91f0a6b258d7e3f019db364b85ab0f5Redox-Active Metal Complexes for Anticancer TherapyZhang, Pingyu; Sadler, Peter J.European Journal of Inorganic Chemistry (2017), 2017 (12), 1541-1548CODEN: EJICFO; ISSN:1434-1948. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The redox properties of both metals and ligands in transition metal complexes offer unusual routes for new mechanisms of anticancer therapy. Metal complexes can introduce artificial reductive and oxidative stress into cancer cells, including behavior as photoactivatable agents and catalysts. Relatively inert metal complexes ("prodrugs") can be activated by redox processes within cancer cells. Examples of pharmaceuticals activated by bioredn. include three PtIV and two RuIII compds. that have already entered clin. trials. More recently, novel CoIII, FeIII, PtIV, Ru(III/II), OsII, and IrIII complexes have been reported to exhibit redox-mediated anticancer activity. Redox activation strategies can introduce new methods to increase cancer cell selectivity and combat drug resistance. Using combination therapy together with redox modulators to increase potency is also possible. This essay focuses on metal complexes that are activated in the reducing environment of cancer cells.350Agdeppa, E. D.; Spilker, M. E. A Review of Imaging Agent Development. AAPS J. 2009, 11, 286– 299, DOI: 10.1208/s12248-009-9104-5[Crossref], [PubMed], [CAS], Google Scholar350https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVWqs7rK&md5=0d2de3edbeae11b64f72cc78586ec93cA review of imaging agent developmentAgdeppa, Eric D.; Spilker, Mary E.AAPS Journal (2009), 11 (2), 286-299CODEN: AJAOB6; ISSN:1550-7416. (Springer)This educational review highlights the processes, opportunities, and challenges encountered in the discovery and development of imaging agents, mainly positron emission tomog. and single-photon emission computed tomog. tracers. While the development of imaging agents parallels the drug development process, unique criteria are needed to identify opportunities for new agents. Imaging agent development has the flexibility to pursue functional or nonfunctional targets as long as they play a role in the specific disease or mechanism of interest and meet imageability requirements. However, their innovation is tempered by relatively small markets for diagnostic imaging agents, intellectual property challenges, radiolabeling constraints, and adequate target concns. for imaging. At the same time, preclin. imaging is becoming a key translational tool for proof of mechanism and concept studies. Pharmaceutical and imaging industries face a common bottleneck in the form of the limited no. of trials one company can possibly perform. However, microdosing and theranostics are evidence that partnerships between pharmaceutical and imaging companies can accelerate clin. translation of tracers and therapeutic interventions. This manuscript will comment on these aspects to provide an educational review of the discovery and development processes for imaging agents.351Miller, A.; Hoogstraten, B.; Staquet, M.; Winkler, A. Reporting Results of Cancer Treatment. Cancer 1981, 47, 207, DOI: 10.1002/1097-0142(19810101)47:1<207::AID-CNCR2820470134>3.0.CO;2-6[Crossref], [PubMed], [CAS], Google Scholar351https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL3M7htFOltw%253D%253D&md5=ced09e34265dc5a574b8cac00362492bReporting results of cancer treatmentMiller A B; Hoogstraten B; Staquet M; Winkler ACancer (1981), 47 (1), 207-14 ISSN:0008-543X.On the initiative of the World Health Organization, two meetings on the Standardization of Reporting Results of Cancer Treatment have been held with representatives and members of several organizations. Recommendations have been developed for standardized approaches to the recording of baseline data relating to the patient, the tumor, laboratory and radiologic data, the reporting of treatment, grading of acute and subacute toxicity, reporting of response, recurrence and disease-free interval, and reporting results of therapy. These recommendations, already endorsed by a number of organizations, are proposed for international acceptance and use to make it possible for investigators to compare validly their results with those of others.352O’Connell, M. PET–CT Modification of RECIST Guidelines. J. Natl. Cancer Inst. 2004, 96, 801, DOI: 10.1093/jnci/djh149[Crossref], [PubMed], [CAS], Google Scholar352https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2c3ltFOhtA%253D%253D&md5=ca24eb9de8435d6ff71317085f1b5e1fPET-CT modification of RECIST guidelinesO'Connell MartinJournal of the National Cancer Institute (2004), 96 (10), 801-2; author reply 802 ISSN:.There is no expanded citation for this reference.353Frank, R. A.; Långström, B.; Antoni, G.; Montalto, M. C.; Agdeppa, E. D.; Mendizabal, M.; Wilson, I. A.; Vanderheyden, J. L. The Imaging Continuum: Bench to Biomarkers to Diagnostics. J. Labelled Compd. Radiopharm. 2007, 50, 746– 769, DOI: 10.1002/jlcr.1444[Crossref], [CAS], Google Scholar353https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht12jsL%252FM&md5=e867959e4c1b01b60d78adc0f551c30dThe imaging continuum: bench to biomarkers to diagnosticsFrank, Richard A.; Longstrom, Bengt; Antoni, Gunnar; Montalto, Michael C.; Agdeppa, Eric D.; Mendizabal, Marivi; Wilson, Ian A.; Vanderheyden, Jean-LucJournal of Labelled Compounds and Radiopharmaceuticals (2007), 50 (9-10), 746-769CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)A review. Innovation in basic and applied science has brought radiotracers to fruition as diagnostics. Non-invasive, longitudinal, and quantifiable mol. imaging is the key to diagnosing and monitoring numerous illnesses, with more to come from characterization of the clin. relevance of findings from genomics research. Radiotracers enable real-time in vivo studies of the effects of drug candidates on receptors, pathways, pharmacodynamics, and clin. relevant endpoints, thereby providing both early detection of pathophysiol. to enable early intervention, and then monitoring of treatment responses to enable individualization of treatment regimens. We review developments which have translated imaging from 'bench to bedside', or 'biomarkers to diagnostics'. Notable developments include (1) synthesis methods for rapid 11C labeling of biomols. to high specific radioactivity; (2) ligand-binding assays for screening mol. imaging agents rather than drugs; (3) in vivo imaging of radiotracers in animals; (4) discovering the imaging advantages of 99mTc, 11C, and 18F; (5) co-registration and automated quant. assessment of high spatial resoln. CT and MR images with mol. images from PET for longitudinal studies of treatment effect.354Robertson, C. A.; Evans, D. H.; Abrahamse, H. Photodynamic Therapy (PDT): A Short Review on Cellular Mechanisms and Cancer Research Applications for PDT. J. Photochem. Photobiol., B 2009, 96, 1– 8, DOI: 10.1016/j.jphotobiol.2009.04.001[Crossref], [PubMed], [CAS], Google Scholar354https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXms1yhtr4%253D&md5=5e72ee20a6629f1eda6e92fb67ef38f7Photodynamic therapy (PDT): A short review on cellular mechanisms and cancer research applications for PDTRobertson, C. A.; Evans, D. Hawkins; Abrahamse, H.Journal of Photochemistry and Photobiology, B: Biology (2009), 96 (1), 1-8CODEN: JPPBEG; ISSN:1011-1344. (Elsevier B.V.)A review. Photodynamic therapy (PDT) has been used for many years, but it is only now becoming widely accepted and utilized. Originally it was developed as a tumor therapy and some of its most successful applications are for non-malignant diseases. This article provides a broad review of different parameters used and mechanisms instituted in PDT such as photosensitizers (PS), photochem. and photophysics, cellular localization, cellular signaling, cell metab. and modes of cell death that operate on a cellular level, as well as photosensitizer pharmacokinetics, biodistribution, tumor localization and modes of tumor destruction. These specific cellular mechanisms are most commonly applied in PDT and for the most part are often researched and exploited. If the combination of these specific parameters and mechanisms can be optimized within PDT it could possibly be used as a suitable alternative for the treatment and management of specific cancers.355Chauhan, P.; Hadad, C.; Sartorelli, A.; Zarattini, M.; Herreros-Lopez, A.; Mba, M.; Maggini, M.; Prato, M.; Carofiglio, T. Nanocrystalline Cellulose–Porphyrin Hybrids: Synthesis, Supramolecular Properties, and Singlet-Oxygen Production. Chem. Commun. 2013, 49, 8525– 8527, DOI: 10.1039/c3cc44852e[Crossref], [PubMed], [CAS], Google Scholar355https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlChurzP&md5=39950e5b3689ee546b1d2276256a25a4Nanocrystalline cellulose-porphyrin hybrids: synthesis, supramolecular properties, and singlet-oxygen productionChauhan, Prashant; Hadad, Caroline; Sartorelli, Andrea; Zarattini, Marco; Herreros-Lopez, Ana; Mba, Miriam; Maggini, Michele; Prato, Maurizio; Carofiglio, TommasoChemical Communications (Cambridge, United Kingdom) (2013), 49 (76), 8525-8527CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)An amino-trisulfonate tetraphenylporphyrin was conjugated to carboxylate cellulose nanocrystals giving rise to a new nanomaterial with interesting binding properties.356Adler, A. D.; Longo, F. R.; Finarelli, J. D.; Goldmacher, J.; Assour, J.; Korsakoff, L. A Simplified Synthesis for Meso-Tetraphenylporphine. J. Org. Chem. 1967, 32, 476, DOI: 10.1021/jo01288a053[ACS Full Text], [CAS], Google Scholar356https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2sXkvVaiu7c%253D&md5=e6a93c80d566eb7a9d2c19f522cf4dbdA simplified synthesis for meso-tetraphenylporphineAdler, Alan D.; Longo, Frederick R.; Finarelli, John D.; Goldmacher, Joel; Assour, Jacques; Korsakoff, LeonardJournal of Organic Chemistry (1967), 32 (2), 476CODEN: JOCEAH; ISSN:0022-3263.A mixt. of pyrrole and BzH is added to refluxing EtCO2H to give cryst. meso-tetraphenylporphine which is purified by mixing with Florex and MeCCl3 or by entrainment sublimation. Cryst. material is not obtained when HOAc is used.357Mannancherril, V.; Therrien, B. Strategies Toward the Enhanced Permeability and Retention Effect by Increasing the Molecular Weight of Arene Ruthenium Metallaassemblies. Inorg. Chem. 2018, 57, 3626– 3633, DOI: 10.1021/acs.inorgchem.7b02668[ACS Full Text], [CAS], Google Scholar357https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVWltLfM&md5=dea6483231ed5a65c92dff84bf61845dStrategies toward the Enhanced Permeability and Retention Effect by Increasing the Molecular Weight of Arene Ruthenium MetallaassembliesMannancherril, Vidya; Therrien, BrunoInorganic Chemistry (2018), 57 (7), 3626-3633CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)The enhanced permeability and retention (EPR) effect is an attractive avenue to target tumors: The size of the drug is the key to accumulating predominantly in tumors. Therefore, to increase the mol. wt. of arene ruthenium metallaassemblies, several strategies can be adopted, and we present here our first step in the design of larger and heavier discrete arene ruthenium metallaassemblies to reach an EPR-size dimension.358Yoo, J. O.; Ha, K. S. New Insights into the Mechanisms for Photodynamic Therapy-Induced Cancer Cell Death. Int. Rev. Cell Mol. Biol. 2012, 295, 139– 174, DOI: 10.1016/B978-0-12-394306-4.00010-1[Crossref], [PubMed], [CAS], Google Scholar358https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFKgsL%252FL&md5=bdc413327941f431668a30ddfa1b4fc3New insights into the mechanisms for photodynamic therapy-induced cancer cell deathYoo, Je-Ok; Ha, Kwon-SooInternational Review of Cell and Molecular Biology (2012), 295 (), 139-174CODEN: IRCMAH; ISSN:1937-6448. (Elsevier Inc.)A review. Photodynamic therapy (PDT) is a promising therapeutic modality for cancer treatment; however, a more detailed understanding is needed to improve the clin. use of this therapy. PDT induces cancer cell death by apoptosis, necrosis, and autophagy, and these mechanisms can be concurrently occurred. PDT destroys cancer cells by inducing apoptosis through diverse signaling pathways coupled with Bcl-2 family members, caspases, and apoptosis-inducing factor. When the apoptotic pathway is unavailable, PDT can cause cancer cell death through induction of a necrotic or autophagic mechanism. Autophagy is occurred in a Bax-independent manner and can be stimulated in parallel with apoptosis. PDT directly destroys cancer cells by inducing either apoptotic or necrotic death. PDT also can induce autophagy as a death or a survival mechanism. These mechanisms are dependent on a variety of parameters including the nature of the photosensitizer, PDT dose, and cell genotype. Understanding the complex cross talk between these pathways may improve the effectiveness of PDT. Here, we discuss the interplay between these mechanisms based on recent evidence and suggest prospects with regard to advances in PDT.359Li, S. Y.; Xie, B. R.; Cheng, H.; Li, C. X.; Zhang, M. K.; Qiu, W. X.; Liu, W. L.; Wang, X. S.; Zhang, X. Z. A Biomimetic Theranostic O2-Meter for Cancer Targeted Photodynamic Therapy and Phosphorescence Imaging. Biomaterials 2018, 151, 1– 12, DOI: 10.1016/j.biomaterials.2017.10.021[Crossref], [PubMed], [CAS], Google Scholar359https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1GktLjM&md5=c3133ddb302d6e7ee32bfc62bc372db4A biomimetic theranostic O2-meter for cancer targeted photodynamic therapy and phosphorescence imagingLi, Shi-Ying; Xie, Bo-Ru; Cheng, Hong; Li, Chu-Xin; Zhang, Ming-Kang; Qiu, Wen-Xiu; Liu, Wen-Long; Wang, Xiao-Shuang; Zhang, Xian-ZhengBiomaterials (2018), 151 (), 1-12CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)In this report, a biomimetic theranostic oxygen (O2)-meter (cancer cell [email protected](II) porphyrinic-metal org. framework, designated as mPPt) was constructed for cancer targeted and phosphorescence image-guided photodynamic therapy (PDT). mPPt presents high photosensitizers (PSs) loading and evitable self-quenching behaviors for favorable biol. O2 sensing and PDT. Besides, endowed by the surface functionalization of cancer cell membrane, the homotypic targeting and immune escape abilities of mPPt could dramatically enhance its cancer targeting ability. Importantly, the O2-dependent phosphorescence responsibility of mPPt could be employed to pre-evaluate the real time O2 level in situ and guide the PDT under light irradn. A significant anticancer effect is obsd. after i.v. injection of mPPt and subsequent treatment with PDT with no obvious side effects. As a versatile platform for cell imaging, O2 fluctuation monitoring as well as PDT, this biomimetic O2-meter exhibits great potential for biol. anal. and personalized cancer theranostics.
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Click to create an ACS IDSTEP 2:
Create a Mendeley accountPlease note: If you switch to a different device, you may be asked to login again with only your ACS ID.
Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.
Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.
MENDELEY PAIRING EXPIRED
Your Mendeley pairing has expired. Please reconnect